Novel cyclic hydrocarbon compounds for the treatment of diseases

ABSTRACT

The invention relates to novel cyclic hydrocarbon compounds and derivatives thereof, processes for the preparation thereof, to said compounds for use as a medicament, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating diseases with said compounds, and to the use of said compounds in the manufacture of medicaments.

FIELD OF THE INVENTION

This invention relates to novel cyclic hydrocarbon compounds andderivatives thereof, processes for the preparation thereof, to saidcompounds for use as a medicament, to said compounds for use in therapy,to pharmaceutical compositions comprising said compounds, to methods oftreating diseases with said compounds, and to the use of said compoundsin the manufacture of medicaments.

BACKGROUND OF THE INVENTION

The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor(GPCR) that signals through the activation of phospholipase C,increasing levels of inositol 1,4,5-triphosphate and cytosolic calcium.The CaSR belongs to the subfamily C of the GPCR superfamily, which alsoincludes receptors for glutamate, gamma aminobutyric acid (GABA),pheromones and odorants that all possess a very large extracellulardomain. This domain is highly negatively charged and is involved inbinding of calcium and other positively charged molecules. The CaSR isfound in the parathyroid glands but has also been identified in thebrain, intestine, pituitary, thyroid glands, bone tissue and kidneys. Inthe parathyroid glands, the CaSR is activated by small increases inextracellular ionized calcium, which inhibits parathyroid hormone (PTH)release from within the stored intracellular granules [Brown, E. M.Calcium-Sensing Receptor. Primer of the Metabolic Bone Diseases andDisorders of Mineral Metabolism Fifth Edition, 2003 by American Societyfor Bone and Mineral Research, Chapter 17, p. 111.; Drueke, T. E.Nephrol Dial Transplant (2004) 19, v20-v26].

In addition to endogenous ligands, small molecule allosteric activatorsof the CaSR (“calcimimetics”) have been developed [Urena, P.; Frazao, J.M. Calcimimetic agents: Review and perspectives. Kidney International(2003), 63, pp. s91-s96; Soudijn, W. et al. Allosteric modulation of Gprotein-coupled receptors: perspectives and recent developments. DDT(2004), 9, 752-758].

The binding site of known calcimimetics is believed to be located in theseven-trans-membrane domain of the receptor [Petrel, C. et al. Journalof Biological Chemistry (2004), 279, 18990-18997].

Calcimimetics have already been shown to be commercially useful for thetreatment of hyperparathyroidism (HPT): The calcimimetic compoundCinacalcet® [Balfour, J. A. B. et al. Drugs (2005) 65(2), 271-281;Linberg et. al. J. Am. Soc. Nephrol (2005), 16, 800-807, ClinicalTherapeutics (2005), 27(11), 1725-1751] has recently been launched forthe treatment of secondary HPT in chronic kidney disease patients ondialysis and for the treatment of primary HPT in patients withparathyroid carcinoma.

Thus, proof of concept for activators of calcium sensing receptor (CaSR)in humans has been achieved and the clinical relevance is already wellestablished.

In chronic kidney disease hypocalcemia results from a disturbance inrenal phosphorus handling and decreased formation of 1,25(OH)-2-VitD. Inresponse, the PTH secretion is increased resulting in a conditionreferred to as secondary HPT. Primary HPT is a hypercalcemic disorderthat results from excessive secretion of PTH usually caused byparathyroid adenoma or primary parathyroid hyperplasia.

Other calcimimetic compounds were for example described in WO 94/018959,WO98/001417, WO05/065050, WO03/099814, WO03/099776, WO00/21910,WO01/34562, WO01/090069, WO97/41090, U.S. Pat. No. 6,001,884,WO96/12697, EP1203761, WO95/11221, WO93/04373, EP1281702, WO02/12181,WO04/069793, US2004242602, WO04/106296 and WO05/115975.

The calcimimetic activity corresponds to the ability to produce orinduce biological responses observed through variations in theconcentration of extracellular calcium ions (Ca²⁺)_(e) and extracellularmagnesium ions (Mg²⁺)_(e).

(Ca²⁺)_(e) and (Mg²⁺)_(e) ions play a major role in the body since theyregulate calcium homeostasis on which the vital functions of the bodydepend. Thus, hypo- and hypercalcemia, that is to say conditions inwhich (Ca²⁺)_(e) ions are below or above the mean threshold, have amajor effect on many functions, such as cardiac, renal or intestinalfunctions. They deeply affect the central nervous system [Chattopadhyayet al. Endocr. Review, (1998)].

CaSRs are proteins which are sensitive to (Ca²⁺)_(e) and (Mg²⁺)_(e)ions, and are present in the parathyroid and thyroid glands, the kidney,the intestine, the lungs, bone cells, the brain, the spinal cord, thepituitary gland, the stomach and keratinocytes [Brown et al, Nature,(1993); Ruat et al, Proc. Natl. Acad. Sci., USA, (1995); Brown et al,Ann. Rev. Med., (1998)]. These proteins are encoded by a single geneisolated from various animal species. They belong to the family of Gprotein-coupled receptors with seven transmembrane domains, and exhibitstructural homologies with metabotropic glutamate receptors, GABAreceptors, and hypothetical pheromone and taste receptors. Activating orinhibitory mutations of the genes in humans are responsible forextremely serious genetic diseases which cause hypocalcemia orhypercalcemia [Pollack et al, Cell, (1993); Pollack et al, NatureGenetic, (1994); Brown et al, Ann. Rev. Med., (1998)]. The functionsassociated with the expression of these proteins in tissues are not yetall known and are the subject of a very great deal of research activity,particularly with regard to the CaSRs present in the parathyroid andthyroid glands, the kidney, the intestine, the spinal cord, the brainand bone cells.

In the parathyroid gland, the CaSRs modulate the secretion ofparathyroid hormone

(PTH), which is the main regulator of calcium homeostasis: an increasein (Ca²⁺)_(e) ions in the serum will activate the CaSRs present on thecells of the parathyroid gland and decrease secretion of the PTHhormone.

The complementary DNA encoding rat CaSR has been isolated from a ratstriatum cDNA library [Ruat et al, Proc. Natl. Acad. Sci., (1995)]. Thisreceptor is identical, in terms of its amino acid sequence, to thatexpressed in the other tissues. Transfected Chinese hamster ovary (CHO)cells expressing rat CaSR(CHO(CaSR)) have been characterized and thechemical signals (second messengers) induced by activation of thisreceptor have been analyzed. Thus, a biochemical test for measuring theaccumulation of tritiated inositol phosphates, [³H]IPs, in response toactivation of the receptor has been developed [Ruat et al, J. Biol.Chem., (1996); Ferry et al, Biochem. Biophys. Res. Common., (1997)]. Ithas been shown that Ca²⁺ and Mg²⁺ ions, but also Ba²⁺ ions, withinmillimolar concentration ranges, stimulate CaSRs. Activation of CaSRsmight be induced in the brain by β-amyloid peptides, which are involvedin neurodegenerative diseases such as Alzheimer's disease [Ye et al, J.Neurosci. Res. (1997)].

Disturbance of CaSR activity is associated with biological disorderssuch as primary and secondary hyperparathyroidism, osteoporosis,cardiovascular, gastrointestinal, endocrine and neurodegenerativediseases, or certain cancers in which (Ca²⁺)_(e) ions are abnormallyhigh.

Secondary hyperparathyroidism is observed in chronic renal failure andis characterized by hyperplasia of the parathyroid glands and anincrease in circulating PTH. The renal failure is also accompanied byrenal osteodystrophy, e.g. osteitis fibrosa, osteomalacia, adynamic bonedisease, or osteoporosis. The disorders are characterized by either highor low bone turnover.

Osteoporosis is a multifactor disease which depends in particular on ageand sex. While menopausal women are very greatly affected, osteoporosisis increasingly proving to be a problem in elderly men, and, for themoment, no really satisfactory treatments exist. Its social cost maybecome even heavier in the years to come, particularly in our Europeansociety where life expectancy is becoming longer. Osteoporosis iscurrently treated with estrogens, calcitonin or biphosphonates whichprevent bone resorption without stimulating bone growth. More recentdata demonstrate that intermittent increases in PTH or in derivativesthereof are effective in the treatment of osteoporosis and make itpossible to remodel bone by stimulating bone formation [Whitfield et al,Drugs & Aging, (1999), Whitfield et al, Calc. Tissue Int., (1999)]. Thisnew therapeutic approach for treatment of osteoporosis appears to bevery advantageous, although major problems are associated with the useof PTH hormone, such as the route of injection, but also the appearanceof tumors, observed recently during clinical trials in humans.Intermittent secretion of endogenous PTH can be obtained by blocking thecalcium sensing receptor. The blocking of PTH secretion with CaSRagonists may be followed by a rapid increase in PTH (rebound effect),which is then beneficial in the treatment of osteoporosis.

SUMMARY OF THE INVENTION

The present invention provides novel cyclic hydrocarbon compounds havingadvantageous calcium sensing receptor (CaSR) modulating effects. It hassurprisingly been found that cyclic hydrocarbon compounds of the presentinvention are modulators, e.g. activators or agonists of the humancalcium sensing receptor (CaSR) and may thus be useful in the treatmentor prophylaxis of a number of diseases or physiological disordersinvolving modulation of CaSR activity.

The cyclic hydrocarbon compounds of the present invention may forexample be useful in the treatment of complications associated withchronic kidney disease, such as hyperparathyroidism, e.g. primary and/orsecondary hyperparathyroidism, or tertiary hyperparathyroidism. Othercomplications associated with chronic kidney disease are anemia,cardiovascular diseases, podocyte-related dysfunction, such asproteinuria, tubular atrophy or podocytopenia, and the compounds of thepresent invention are also believed to have a beneficial effect on thesediseases. The cyclic hydrocarbon compounds of the present invention mayfurthermore be useful for promoting osteogenesis and treating orpreventing osteoporosis, such as steroid induced, senile and postmenopausal osteoporosis; osteomalacia and related bone disorders, or forthe prevention of bone loss post renal transplantation, or in rescuetherapy pre-parathyroidectomy.

It is presently believed that the cyclic hydrocarbon compounds of thepresent invention may have advantageous pharmacokinetic orpharmacodynamic properties, such as oral bioavailability, in comparisonto known structurally related compounds.

Accordingly, the present invention relates to a compound of generalformula I

wherein

represents cycloalkyl comprising 4-7 carbon atoms optionally beingsubstituted with one or more, same of different substitutents selectedfrom R₂, R₃, R₄ or R₅;A represents C₁₋₁₀heteroaryl, C₆₋₁₄aryl or C₆₋₁₀heterocycloalkylaryl,each of which are optionally substituted with one or more, same ordifferent substituents represented by halogen, hydroxy, mercapto,trifluoromethyl, cyano, carboxy, —NH₂, —C(O)NH₂, nitro, oxo, —S(O)₂NH₂,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄hydroxyalkyl, C₁₋₆haloalkyl,C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkylcarbonyloxy,C₁₋₄alkoxycarbonyloxy, C₁₋₄alkoxysulfonyloxy, C₁₋₄alkoxycarbamoyl,C₁₋₄-aminocarbonyl, C₁₋₄alkylthio, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,C₁₋₆-amino, iminomethyl, C₁₋₄-aminosulfonyl, C₁₋₄-aminocarbonyloxy,C₁₋₄alkylsulfonylamino, hydroxyiminomethyl, C₁₋₄alkylcarbonylamino,C₁₋₄alkylsulfonyl, C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl,C₁₋₁₀heteroaryl or C₆₋₁₄aryl,wherein said C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkylcarbonyloxy,C₁₋₄alkoxycarbonyloxy, C₁₋₄alkoxysulfonyloxy, C₁₋₄alkoxycarbamoyl,C₁₋₄-aminocarbonyl, C₁₋₄alkylthio, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl,C₁₋₆-amino, iminomethyl, C₁₋₄-aminosulfonyl, C₁₋₄aminocarbonyloxy,C₁₋₄alkylsulfonylamino, hydroxyiminomethyl, C₁₋₄alkylcarbonylamino,C₁₋₄alkylsulfonyl, C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl,C₁₋₁₀heteroaryl or C₆₋₁₄aryl,are optionally further substituted with one or more, same or differentsubstituents selected from halogen, hydroxy, —NH₂, mercapto,trifluoromethyl, cyano, carboxy, —C(O)NH₂, nitro, oxo, —S(O)₂NH₂,C₁₋₄alkyl, C₁₋₆haloalkyl, C₁₋₃alkoxy or C₁₋₃hydroxyalkyl;R₁ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆hydroxyalkyl,C₁₋₆haloalkyl, C₁₋₆alkylamino, C₃₋₆cycloalkyl, or C₁₋₆heterocycloalkyl,each of which are optionally substituted with one or more, same ordifferent substituents selected from halogen, hydroxy, mercapto,trifluoromethyl, cyano, carboxy, NH₂, —C(O)NH₂, nitro, oxo, C₁₋₃alkyl,C₂₋₄alkenyl, C₁₋₃hydroxyalkyl, C₁₋₃haloalkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl or C₁₋₄amino;R₂ and R₃ independently of each other represent hydrogen, cyano,halogen, carboxy, —C(O)NH₂, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆hydroxyalkyl, aminoC₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆heterocycloalkyl,C₁₋₆alkoxy, C₁₋₆-aminocarbonyl, C₆₋₁₀aryloxycarbonyl, C₁₋₆amino,C₆₋₁₀arylamino, C₁₋₄alkoxycarbonylamino, C₁₋₄alkylcarbonylamino,C₂₋₄alkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino orC₁₋₆heterocycloalkylcarbonylamino,wherein said —C(O)NH₂, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆hydroxyalkyl,C₁₋₆haloalkyl, aminoC₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆heterocycloalkyl,C₁₋₆alkoxy, C₁₋₆aminocarbonyl, C₆₋₁₀aryloxycarbonyl, C₁₋₆amino,C₆₋₁₀arylamino, C₁₋₄alkoxycarbonylamino, C₁₋₄alkylcarbonylamino,C₂₋₄alkenylcarbonylamino, C₃₋₄cycloalkylcarbonylamino orC₁₋₆heterocycloalkylcarbonylamino, are optionally substituted with oneor more, same or different substituents represented by halogen, hydroxy,mercapto, trifluoromethyl, cyano, carboxy, —NH₂, —C(O)NH₂, nitro,C₁₋₃alkyl, C₂₋₄alkenyl, C₁₋₃hydroxyalkyl, C₁₋₃haloalkyl,C₁₋₄alkoxycarbonyl or C₁₋₄amino;R₄ represents hydrogen, halogen, hydroxy, carboxy, —NH₂, —C(O)NH₂,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆hydroxyalkyl, C₁₋₆haloalkyl,aminoC₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆heterocycloalkyl,C₁₋₆alkoxycarbonyl, C₁₋₆aminocarbonyl, C₆₋₁₀aryloxycarbonyl,C₁₋₁₀heteroaryloxycarbonyl, C₁₋₆amino, C₆₋₁₀arylamino,C₁₋₆heteroarylamino, C₆₋₁₀arylC₁₋₆amino, C₁₋₄alkoxycarbonylamino,C₁₋₄alkylcarbonylamino, C₂₋₄alkenylcarbonylamino,C₃₋₆cycloalkylcarbonylamino or C₁₋₆heterocycloalkylcarbonylamino,wherein said —C(O)NH₂, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆hydroxyalkyl, C₁₋₆haloalkyl, aminoC₁₋₆alkyl, C₃₋₆cycloalkyl,C₁₋₆heterocycloalkyl, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, C₁₋₆aminocarbonyl,C₆₋₁₀aryloxycarbonyl, C₁₋₁₀heteroaryloxycarbonyl, C₁₋₆amino,C₆₋₁₀arylamino, C₁₋₁₀heteroarylamino, C₆₋₁₀arylC₁₋₆amino,C₁₋₄alkoxycarbonylamino, C₁₋₄alkylcarbonylamino,C₂₋₄alkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino orC₁₋₆heterocycloalkylcarbonylamino,are optionally substituted with one or more, same or differentsubstituents represented by halogen, hydroxy, mercapto, trifluoromethyl,cyano, carboxy, —NH₂, hydroxyiminomethyl, —C(O)NH₂, nitro, C₁₋₃alkyl,C₂₋₄alkenyl, C₁₋₃hydroxyalkyl, C₁₋₃haloalkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl or C₁₋₄amino;each of R₅ represents independently one or more same or differentsubstituents represented by hydrogen, halogen, hydroxy, carboxy, —NH₂,—C(O)NH₂, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆hydroxyalkyl,C₃₋₆cycloalkyl, C₁₋₆heterocycloalkyl, C₁₋₆alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₆aminocarbonyl, C₆₋₁₀aryloxycarbonyl, C₁₋₁₀heteroaryloxycarbonyl,C₁₋₆amino, C₆₋₁₀aryl, C₆₋₁₀arylamino, C₁₋₁₀heteroarylamino,C₆₋₁₀arylcarbonylamino, C₁₋₄alkoxycarbonylamino, C₆₋₁₀arylsulfonylamino,C₁₋₄alkylcarbonylamino, C₂₋₄alkenylcarbonylamino,C₃₋₆cycloalkylcarbonylamino or C₁₋₆heterocycloalkylcarbonylamino,wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆hydroxyalkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₁₋₆heterocycloalkyl, C₁₋₆alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₆aminocarbonyl, C₆₋₁₀aryloxycarbonyl,C₁₋₁₀heteroaryloxycarbonyl, C₁₋₆amino, C₆₋₁₀aryl, C₆₋₁₀arylamino,C₁₋₁₀heteroarylamino, C₆₋₁₀arylcarbonylamino, C₁₋₄alkoxycarbonylamino,C₆₋₁₀arylsulfonylamino, C₁₋₄alkylcarbonylamino,C₂₋₄alkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino orC₁₋₆heterocycloalkylcarbonylamino,are optionally further substituted with one or more, same or differentsubstituents selected from halogen, hydroxy, mercapto, cyano,trifluoromethyl, carboxy, —NH₂, —C(O)NH₂, nitro, oxo, C₁₋₃alkyl,C₂₋₄alkenyl, C₁₋₃hydroxyalkyl, C₁₋₃haloalkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, iminomethyl or hydroxyiminomethyl;G represents hydrogen, —C(O)H, —C(O)NH₂, —O—C(O)NH₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆hydroxyalkyl, C₁₋₆haloalkyl, C₁₋₆amino,C₃₋₈cycloalkyl, C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl,C₃₋₈cycloalkenyl, C₆₋₁₄aryl, C₁₋₁₀heteroaryl, C₆₋₁₀arylamino,hydroxyaminocarbonyl, C₆₋₁₀arylaminocarbonyl, C₁₋₄aminocarbonyl,C₁₋₆heterocycloalkylcarbonyl, C₁₋₁₀heteroarylaminocarbonyl,C₆₋₁₀arylsulfonylaminocarbonyl, C₆₋₁₄aryloxy, C₆₋₁₀heteroaryloxy,C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkylcarbonyloxy,C₁₋₄alkoxycarbonyloxy, C₁₋₆aminocarbonyloxy, C₁₋₁₀heteroarylamino,C₁₋₃alkylcarbonylamino, C₆₋₁₀arylcarbonylamino,C₃₋₆cycloalkylcarbonylamino, C₁₋₄alkoxycarbonylamino,C₁₋₆heterocycloalkylcarbonylamino or ureido,wherein said —C(O)H, —C(O)NH₂, —O—C(O)NH₂, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆hydroxyalkyl, C₁₋₆haloalkyl, C₁₋₆amino, C₃₋₈cycloalkyl,C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl, C₃₋₈cycloalkenyl,C₆₋₁₄aryl, C₁₋₁₀heteroaryl, C₆₋₁₀arylamino, hydroxyaminocarbonyl,C₆₋₁₀arylaminocarbonyl, C₁₋₄aminocarbonyl, C₁₋₆heterocycloalkylcarbonyl,C₁₋₁₀heteroarylaminocarbonyl, C₁₋₁₀arylsulfonylaminocarbonyl,C₆₋₁₄aryloxy, C₁₋₁₀heteroaryloxy, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy, C₁₋₆aminocarbonyloxy,C₁₋₁₀heteroarylamino, C₁₋₃alkylcarbonylamino, C₆₋₁₀arylcarbonylamino,C₃₋₆cycloalkylcarbonylamino, C₁₋₄alkoxycarbonylamino,C₁₋₆heterocycloalkylcarbonylamino or ureido,are optionally further substituted with one or more, same or differentsubstituents represented by halogen, cyano, carboxy, —NH₂, C₁₋₆amino,iminomethyl, hydroxyiminomethyl, amidino, hydroxy, mercapto, —C(O)H,—C(O)NH₂, nitro, oxo, trifluoromethyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄hydroxyalkyl, aminoC₁₋₃alkyl, C₁₋₆haloalkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkylcarbonyl, C₁₋₄aminocarbonyl,hydroxyaminocarbonyl, C₃₋₆cycloalkylaminocarbonyl,C₁₋₆heterocycloalkylaminocarbonyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl,C₁₋₆cycloalkylamino, C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl,C₁₋₆heterocycloalkylcarbonyl, C₆₋₁₄aryl, carboxyC₆₋₁₀aryl,C₁₋₆heteroaryl, C₁₋₆heteroarylaminocarbonyl, —S(O)₂NH₂, C₁₋₆ureido,C₁₋₆thioureido, C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy,C₁₋₄alkoxysulfonyloxy, C₁₋₆heterocycloalkyloxy, C₁₋₄aminosulfonyl,C₁₋₄aminocarbonyloxy, C₁₋₄alkylsulfonylamino, C₆₋₁₀arylamino,C₆₋₁₀arylaminocarbonyl, C₆₋₁₀aryloxycarbonyl, C₁₋₄alkoxycarbamoyl,C₆₋₁₀arylcarbonylamino, C₆₋₁₀arylsulfonylamino, C₁₋₄alkylcarbonylamino,C₁₋₄alkenylcarbonylamino, C₃₋₆cycloalkenylcarbonylamino,C₁₋₆cycloalkylcarbonylamino, C₁₋₄alkoxycarbonylamino,C₁₋₆heterocycloalkylcarbonylamino, C₁₋₄alkylsulfonyl,C₁₋₆heterocycloalkylsulfonyl or C₁₋₃alkylsulfonylaminocarbonyl,wherein said carboxy, C₁₋₆amino, iminomethyl, hydroxyiminomethyl,C(O)NH₂, C₁₋₆alkyl, C₂₋₄alkenyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄hydroxyalkyl, aminoC₁₋₃alkyl, C₁₋₆haloalkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkylcarbonyl, C₁₋₄aminocarbonyl,hydroxyaminocarbonyl, C₃₋₆cycloalkylaminocarbonyl,C₁₋₆heterocycloalkylaminocarbonyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl,C₁₋₆cycloalkylamino, C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl,C₁₋₆heterocycloalkylcarbonyl, C₆₋₁₄aryl, carboxyC₆₋₁₀aryl,C₁₋₆heteroaryl, C₁₋₆heteroarylaminocarbonyl, —S(O)₂NH₂, C₁₋₆ureido,C₁₋₆thioureido, C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy,C₁₋₄alkoxysulfonyloxy, C₁₋₆heterocycloalkyloxy, C₁₋₄alkylthio,C₁₋₄aminosulfonyl, C₁₋₄aminocarbonyloxy, C₁₋₄alkylsulfonylamino,C₆₋₁₀arylamino, C₆₋₁₀arylaminocarbonyl, C₆₋₁₀aryloxycarbonyl,C₁₋₄alkoxycarbamoyl, C₆₋₁₀arylcarbonylamino, C₆₋₁₀arylsulfonylamino,C₁₋₄alkylcarbonylamino, C₁₋₄alkenylcarbonylamino,C₃₋₆cycloalkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino,C₁₋₄alkoxycarbonylamino, C₁₋₆heterocycloalkylcarbonylamino,C₁₋₄alkylsulfonyl, C₁₋₆heterocycloalkylsulfonyl orC₁₋₃alkylsulfonylaminocarbonyl,are optionally further substituted with one or more, same or differentsubstituents selected from hydroxy, —NH₂, C₁₋₆amino, iminomethyl,hydroxyiminomethyl, carboxy, trifluoromethyl, halogen, oxo, mercapto,cyano, —C(O)NH₂, nitro, C₁₋₆alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄hydroxyalkyl, C₁₋₆haloalkyl, C₁₋₃alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₄alkylcarbonyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,C₁₋₆heterocycloalkyl, C₆₋₁₂aryl, C₁₋₁₀heteroaryl, C₁₋₃alkoxyC₆₋₁₀aryl,C₁₋₁₀heterocycloalkylaryl, C₁₋₆heterocycloalkenyl, —S(O)₂NH₂, —S(O)₂OH,—S(O)₂CH₃, C₁₋₆ureido, C₁₋₆thioureido, C₁₋₄alkylcarbonyloxy,C₁₋₄alkoxycarbonyloxy, C₁₋₄alkoxysulfonyloxy, C₁₋₄alkoxycarbamoyl,C₁₋₄aminocarbonyl, C₁₋₆heterocycloalkylcarbonyl, C₁₋₄alkylthio,C₁₋₄aminosulfonyl, C₁₋₄aminocarbonyloxy, C₁₋₄alkylsulfonylamino,C₆₋₁₄arylsulfonyl, C₆₋₁₀arylsulfonylamino, hydroxyiminomethyl,C₁₋₄alkylcarbonylamino or C₁₋₄alkylsulfonyl,wherein said —C(O)NH₂, C₁₋₆amino, C₁₋₆alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄hydroxyalkyl, C₁₋₆haloalkyl, C₁₋₃alkoxy, C₁₋₄alkoxycarbonyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, C₁₋₆heterocycloalkyl, C₆₋₁₂aryl,C₁₋₁₀heteroaryl, C₁₋₃alkoxyC₆₋₁₀aryl, C₁₋₁₀heterocycloalkylaryl,C₁₋₆heterocycloalkenyl, —S(O)₂NH₂, —S(O)₂OH, C₁₋₆ureido, C₁₋₆thioureido,C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy, C₁₋₄alkoxysulfonyloxy,C₁₋₄alkoxycarbamoyl, C₁₋₄aminocarbonyl, C₁₋₆heterocycloalkylcarbonyl,C₁₋₄alkylthio, C₁₋₄aminosulfonyl, C₁₋₄aminocarbonyloxy,C₁₋₄alkylsulfonylamino, C₆₋₁₄arylsulfonyl, C₆₋₁₀arylsulfonylamino,hydroxyiminomethyl, C₁₋₄alkylcarbonylamino or C₁₋₄alkylsulfonyl, areoptionally further substituted with one or more, same or differentsubstituents selected from hydroxy, oxo, cyano, halogen,trifluoromethyl, C₁₋₃alkoxy, C₁₋₃alkoxyC₁₋₃alkoxy, C₁₋₆amino, mercapto,carboxy, —C(O)NH₂, nitro, C₁₋₆alkyl, C₁₋₃hydroxyalkyl,C₁₋₄alkoxycarbonyl, C₁₋₃alkylcarbonylamino, C₁₋₆heterocycloalkyl,C₆₋₁₂aryl, C₁₋₆heteroaryl, —S(O)₂NH₂ or —S(O)₂OH;or G, together with R₄, forms an oxo group;provided that the compound is not

-   N-cyclopentyl-α-methyl-benzenemethanamine,-   N-cyclohexyl-α-methyl-benzenemethanamine,-   3-[3-[(1-phenylethyl)amino]cyclohexyl]-phenol,-   2-[3-[3-[(1-phenylethyl)amino]cyclohexyl]phenoxy]-ethylester acetic    acid,-   N-[3-(3-methoxyphenyl)cyclohexyl]-α-methyl-2-naphthalenemethanamine,-   N-[3-(3-methoxyphenyl)cyclohexyl]-α-methyl-benzenemethanamine,-   N-cyclohexyl-α-methyl-1-naphthalenennethanamine,-   3-methoxy-α-methyl-N-(2-phenylcyclohexyl)-benzenemethanamine,-   3-methoxy-α-methyl-N-(3-phenylcyclohexyl)-benzenemethanamine,-   3-methoxy-α-methyl-N-(4-phenylcyclohexyl)-benzenemethanamine,-   4-chloro-N-cyclohexyl-α-methyl-benzenemethanamine,-   N-(1-phenylethyl)-cycloheptanamine,    or a pharmaceutically acceptable salt, solvate or in vivo    hydrolysable ester thereof.

In another aspect, the present invention relates to a compound offormula I as defined herein for use as a medicament in therapy.

In yet another aspect, the present invention relates to a compound offormula I as defined herein or compound

-   N-cyclopentyl-α-methyl-benzenemethanamine,-   N-cyclohexyl-α-methyl-benzenemethanamine,-   3-[3-[(1-phenylethyl)amino]cyclohexyl]-phenol,-   2-[3-[3-[(1-phenylethyl)amino]cyclohexyl]phenoxy]-, ethyl ester,    acetic acid,-   N-[3-(3-methoxyphenyl)cyclohexyl]-α-methyl-2-naphthalenemethanamine,-   N-[3-(3-methoxyphenyl)cyclohexyl]-α-methyl-benzenemethanamine,-   N-cyclohexyl-α-methyl-1-naphthalenemethanamine,-   4-chloro-N-cyclohexyl-α-methyl-benzenemethanamine, or-   N-(1-phenylethyl)-cycloheptanamine,    for use in the treatment, amelioration or prophylaxis of    physiological disorders or diseases associated with disturbances of    CaSR activity, such as hyperparathyroidism.

In a further aspect, the invention relates to the use of a compound ofgeneral formula I as defined herein or compound

-   N-cyclopentyl-α-methyl-benzenemethanamine,-   N-cyclohexyl-α-methyl-benzenemethanamine,-   3-[3-[(1-phenylethyl)amino]cyclohexyl]-phenol,-   2-[3-[3-[(1-phenylethyl)amino]cyclohexyl]phenoxy]-, ethyl ester,    acetic acid,-   N-[3-(3-methoxyphenyl)cyclohexyl]-α-methyl-2-naphthalenemethanamine,-   N-[3-(3-methoxyphenyl)cyclohexyl]-α-methyl-benzenemethanamine,-   N-cyclohexyl-α-methyl-1-naphthalenemethanamine,-   4-chloro-N-cyclohexyl-α-methyl-benzenemethanamine, or-   N-(1-phenylethyl)-cycloheptanamine,    for the manufacture of a medicament for the prophylaxis, treatment    or amelioration of physiological disorders or diseases associated    with disturbances of CaSR activity, such as hyperparathyroidism.

In a still further aspect, the invention relates to a pharmaceuticalcomposition comprising a compound of formula I as defined herein or apharmaceutically acceptable salt, solvate, or in vivo hydrolysable esterthereof together with a pharmaceutically acceptable excipient orvehicle.

In a still further aspect, the invention relates to a method ofpreventing, treating or ameliorating parathyroid carcinoma, parathyroidadenoma, primary parathyroid hyperplasia, cardiac, renal or intestinaldisfunctions, diseases of the central nervous system, chronic renalfailure, chronic kidney disease, primary hyperparathyroidism, secondaryhyperparathyroidism, tertiary hyperparathyroidism, anemia,cardiovascular diseases, osteitis fibrosa, adynamic bone disease,osteoporosis, steroid induced osteoporosis, senile osteoporosis, postmenopausal osteoporosis, osteomalacia and related bone disorders, boneloss post renal transplantation, gastrointestinal diseases, endocrineand neurodegenerative diseases, cancer, Alzheimer's disease,hypercalcemia, or renal bone diseases, the method comprisingadministering to a patient in need thereof an effective amount of acompound of general formula I as defined herein, optionally incombination or as supplement with an active vitamin-D sterol orvitamin-D derivative, such as 1-α-hydroxycholecalciferol,ergocalciferol, cholecalciferol, 25-hydroxycholecalciferol,1-α-25-dihydroxycholecalciferol, or in combination or as supplement withphosphate binders, estrogens, calcitonin or biphosphonates.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “cycloalkyl” is intended to indicate a saturated cycloalkaneradical, comprising 3-8 carbon atoms, such as 4-7 or 3-6 carbon atoms,such as 4-6 or preferably 5-6 carbon atoms, e.g. cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term

is intended to indicate a saturated cycloalkane radical, comprising 4-7carbon atoms, such as 4-6 or 5-6 carbon atoms, preferably 5 carbon atomsor 6 carbon atoms, e.g. cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl.

The term “cycloalkenyl” is intended to indicate a mono-, or diunsaturated non-aromatic cyclic hydrocarbon radical, comprising 3-8carbon atoms, such as 4-7, such as 3-6 carbon atoms, such as 4-6 orpreferably 5-6 carbon atoms, e.g. cyclobutenyl, cyclopentenyl, orcyclohexenyl.

The term “heterocycloalkyl” is intended to include a cycloalkyl radicalas defined above, comprising 1-7 carbon atoms, such as 1-6 carbon atoms,in particular a 4-, 5- or 6-membered ring, comprising 2-5 carbon atomsand 1-5 hetero atoms (selected from O, S and N), such as 3-5 carbonatoms and 1-3 hetero atoms, preferably 4-5 carbon atoms and 1-2 heteroatoms selected from O, S, or N, e.g. morpholino, morpholinyl,pyrrolidinyl, oxo-pyrrolidinyl, piperidino, azetidinyl,tetrahydro-furyl, tetrahydro-pyranyl, oxo-tetrahydro-furyl,oxo-oxazolidinyl, oxetanyl, dioxo-imidazolidinyl, piperidyl orpiperazinyl.

The term “heterocycloalkenyl” is intended to indicate a cycloalkenylradical as defined above, comprising 1-7 carbon atoms, such as 1-6carbon atoms, in particular a 5- or 6-membered ring, comprising 1-5carbon atoms and 1-5 hetero atoms (selected from O, S and N), such as3-5 carbon atoms and 1-3 hetero atoms, preferably 4-5 carbon atoms and1-2 hetero atoms selected from O, S, or N.

The term “heterocycloalkyloxy” is intended to include a radical of theformula —OR, wherein R represents heterocycloalkyl as defined above,e.g. oxo-dihydro-furyloxy.

The term “heterocycloalkylaryl” is intended to include radicals of (a)heterocycloalkyl ring(s), in particular 5- or 6-membered ring,comprising 1-5 carbon atoms and 1-4 heteroatoms, selected from O, N orS, such as 1-5 carbon atoms and 1-3 heteroatoms, preferably 2-5 carbonatoms and 1-2 heteroatoms, the heterocycloalkyl ring being fused orannelated with one or more aromatic carbocyclic rings comprising 6-10carbon atoms, such as phenyl or naphthyl.

The term “aryl” is intended to indicate a radical of (an) aromaticcarbocyclic ring(s) comprising 6-20 carbon atoms, such as 6-14 carbonatoms, preferably 6-10 carbon atoms, in particular 6-membered rings,optionally fused or annelated carbocyclic rings with at least onearomatic ring, e.g. phenyl, naphthyl, 1-naphthyl or indanyl.

The term “heteroaryl” is intended to include radicals of (a)heterocyclic aromatic ring(s), comprising 1-4 heteroatoms (selected fromO, S and N) and 1-10 carbon atoms, such as 1-3 heteroatoms and 1-6carbon atoms, such as 1-3 heteroatoms and 2-5 carbon atoms, such as 1-2heteroatoms and 3-5 carbon atoms, preferably 5- or 6-membered rings with1-3 heteroatoms and 2-5 carbon atoms or 1-3 heteroatoms and 2-4 carbonatoms selected from O, S and N, e.g. pyridyl, thiazolyl, imidazolyl,isoxadiazolyl, [1,2,4]oxadiazolyl, oxazolyl, pyrazolyl, indolyl,thienyl, furyl, 1-benzo[b]thiophenyl, 2,3-dihydro-benzo[1,4]dioxinyl, or2,3-dihydro-benzofuryl.

The term “halogen” is intended to indicate a substituent from the 7^(th)main group of the periodic table, preferably fluoro, chloro, iodo orbromo.

In the present context, the term “alkyl” is intended to indicate theradical obtained when one hydrogen atom is removed from a hydrocarbon.Said alkyl comprises 1-6, preferably 1-4 or 1-3, such as 2-4 or 1-2carbon atoms. The term includes the subclasses normal alkyl (n-alkyl),secondary and tertiary alkyl, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,hexyl or isohexyl.

The term “alkenyl” is intended to indicate a mono-, di-, ortriunsaturated hydrocarbon radical comprising 2-6 carbon atoms, inparticular 2-4 carbon atoms, such as 2-3 carbon atoms, e.g. vinyl,allyl, propenyl, butenyl, pentenyl or hexenyl.

The term “alkynyl” is intended to indicate a hydrocarbon radicalcomprising 1-4 C—C triple bonds, e.g. 1, 2 or 3 triple bonds and 2-6carbon atoms, the alkane chain typically comprising 2-5 carbon atoms, inparticular 2-4 carbon atoms, such as 2-3 carbon atoms, e.g. ethynyl,propynyl, butynyl or pentynyl.

The term “hydroxyalkyl” is intended to indicate an alkyl radical asdefined above, wherein one, two, three or more hydrogen atoms arereplaced by hydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl etc.

The term “haloalkyl” is intended to indicate an alkyl radical as definedabove, wherein one, two, three or more hydrogen atoms are replaced byhalogen, same or different, such as iodo, chloro, bromo and/or fluoro,e.g. fluoroethyl, difluoroethyl, difluoromethyl or trifluoromethyl.

The term “aminoalkyl” in intended to indicate an alkyl radical asdefined above wherein one or two hydrogen atoms are replaced by —NH₂,e.g. aminomethyl, aminoethyl or aminopropyl.

The term “aminocarbonyl” is intended to indicate a radical of theformula —C(O)—NRR′,

wherein R and R′ independently represents hydrogen, alkyl, cycloalkyl oralkenyl as indicated above, e.g. aminocarbonyl, methylaminocarbonyl,ethylaminocarbonyl, propylaminocarbonyl, tert-butylaminocarbonyl,cyclopropylaminocarbonyl, isopropylaminocarbonyl,sec-butylaminocarbonyl, methylethylaminocarbonyl, dimethylaminocarbonylor diethylaminocarbonyl.

The term “alkylcarbonyl” is intended to indicate a radical of theformula —C(O)—R, wherein R represents alkyl as indicated above, e.g.methylcarbonyl, ethylcarbonyl.

The term “alkoxy” is intended to indicate a radical of the formula —OR,wherein R is alkyl or alkenyl as indicated above, e.g. methoxy, ethoxy,n-propoxy, isopropoxy, butoxy, tert-butoxy, etc.

The term “alkoxyalkoxy” is intended to indicate a radical of the formula—OR—OR, wherein R is alkyl or alkenyl as indicated above, e.g.methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, etc.

The term “alkoxycarbonyl” is intended to indicate a radical of theformula —C(O)—O—R, wherein R is alkyl as indicated above, e.g.methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl etc.

The term “alkylcarbonyloxy” is intended to indicate a radical of theformula —O—C(O)—R, wherein R is alkyl as indicated above, e.g.methylcarbonyloxy, or ethylcarbonyloxy.

The term “alkoxycarbamoyl” is intended to indicate a radical of theformula —C(O)NR′—O—R, wherein R′ is hydrogen or alkyl as indicatedabove, and R is alkyl as indicated above, e.g. methoxycarbamoyl,tert-butoxycarbamoyl.

The term “amino” is intended to indicate a radical of the formula —NRR′,wherein R and R′ independently represent hydrogen, alkyl or alkenyl, asindicated above, e.g. —NH₂, methylamino, ethylamino, propylamino,dimethylamino, diethylamino, isopropylamino, sec-butylamino,tert-butylamino or ethylmethylamino.

The term “cycloalkylamino” is intended to indicate a radical of theformula —NRR′, wherein R represents hydrogen or alkyl and R′ representscycloalkyl as indicated above, e.g. cyclopropylamino.

The term “arylamino” is intended to indicate a radical of the formula—NRR′, wherein R represents hydrogen or alkyl as inducated above and R′represents aryl as indicated above, e.g. phenylamino or indalylamino.

The term “alkoxyaryl” is intended to indicate a radical of the formula—Ar—O—R, wherein Ar represents aryl as indicated above and R representsalkyl as indicated above, e.g. methoxyphenyl or ethoxyphenyl.

The term “carboxyaryl” is intended to indicate a radical of the formula—Ar—C(O)OH, wherein Ar represents aryl as indicated above, e.g.carboxyphenyl.

The term “heteroarylamino” is intended to indicate a radical of theformula —NRR′, wherein R represents hydrogen or alkyl as indicatedabove, and R′ represents heteroaryl as indicated above.

The term “heterocycloalkylcarbonyl” is intended to indicate a radical ofthe formula —C(O)—R, wherein R is heterocycloalkyl as indicated below,e.g. piperidylcarbonyl, morpholinocarbonyl, morpholinylcarbonyl,piperazinylcarbonyl, pyrrolidinylcarbonyl, oxo-pyrrolidinylcarbonyl,piperidinocarbonyl or azetidinylcarbonyl.

The term “aminocarbonyl” is intended to indicate a radical of theformula —C(O)—NR′₂, wherein each R′ is independently hydrogen, alkyl,alkenyl or cycloalkyl as indicated above, e.g. carbamoyl,methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl,diethylaminocarbonyl, ethylmethylaminocarbonyl,methylethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl,butylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl,cyclopropylaminocarbonyl or cyclohexylaminocarbonyl.

The term “hydroxyaminocarbonyl” is intended to indicate a radical of theformula —C(O)—NR′-OH, wherein R′ is independently hydrogen or alkyl asindicated above.

The term “arylaminocarbonyl” is intended to indicate a radical of theformula —C(O)—NR′-aryl, wherein R′ is independently hydrogen or alkyl asindicated above and aryl is as indicated above, e.g.phenylaminocarbonyl, indanylaminocarbonyl.

The term “heteroarylaminocarbonyl” is intended to indicate a radical ofthe formula —C(O)—NR′-heteroaryl, wherein R′ is independently hydrogenor alkyl as indicated above and heteroaryl is as indicated above, e.g.pyrazolylaminocarbonyl, pyridylaminocarbonyl.

The term “cycloalkylaminocarbonyl” is intended to indicate a radical ofthe formula —C(O)—NR′-cycloalkyl, wherein R′ is independently hydrogenor alkyl as indicated above and “cycloalkyl is as indicated above, e.g.cyclopropylaminocarbonyl, cyclobutylaminocarbonyl,cyclopentylaminocarbonyl or cyclohexylaminocarbonyl.

The term “heterocycloalkylaminocarbonyl” is intended to indicate aradical of the formula —C(O)—NR′-heterocycloalkyl, wherein R′ isindependently hydrogen or alkyl as indicated above and heterocycloalkylis as indicated above, e.g. tetrahydrofurylaminocarbonyl oroxo-tetrahydrofurylaminocarbonyl.

The term “alkylsulfonylaminocarbonyl” is intended to indicate a radicalof the formula —C(O)—NR′—S(O)₂—R, wherein R′ is independently hydrogen,alkyl or cycloalkyl as indicated above and R is alkyl as indicatedabove, e.g. methylsulfonylaminocarbonyl.

The term “aryloxy” is intended to indicate a radical of the formula—O—R, wherein R is aryl as indicated above, e.g. phenyloxy.

The term “aryloxycarbonyl” is intended to indicate a radical of theformula —C(O)—O—R wherein R is aryl as indicated above, e.g.phenyloxycarbonyl.

The term “heteroaryloxy” is intended to indicate a radical of theformula —O—R, wherein R is heteroaryl as indicated above.

The term “heteroaryloxycarbonyl” is intended to indicate a radical ofthe formula —C(O)—O—R, wherein R is heteroaryl as indicated above.

The term “alkylthio” is intended to indicate a radical of the formula—S—R, wherein R is alkyl as indicated above.

The term “iminomethyl” is intended to indicate the radical —CH═NH.

The term “hydroxyiminomethyl” is intended to indicate the radical—CH═N—(OH).

The term “aminosulfonyl” is intended to indicate a radical of theformula —S(O)₂—NR₂, wherein each R independently represents hydrogen, oralkyl as indicated above, e.g. ethylaminosulfonyl.

The term “alkylsulfonyl” is intended to indicate a radical of theformula —S(O)₂—R, wherein R is alkyl as indicated above.

The term “arylsulfonyl” is intended to indicate a radical of the formula—S(O)₂—R, wherein R is aryl as indicated above, e.g. phenylsulfonyl.

The term “heterocycloalkylsulfonyl” is intended to indicate a radical ofthe formula —S(O)₂—R, wherein R is a heterocycloalkyl as indicatedabove, e.g. morpholinesulfonyl.

The term “aminocarbonyloxy” is intended to indicate a radical of theformula —O—C(O)—NRR′, wherein R and R′ independently represent hydrogenor alkyl as indicated above.

The term “alkylcarbonylamino” is intended to indicate a radical of theformula —NR′—C(O)—R, wherein R′ is hydrogen or alkyl as indicated above,and R is alkyl as indicated above, e.g. methylcarbonylamino.

The term “alkoxycarbonylamino” is intended to indicate a radical of theformula —NR′—C(O)—O—R, wherein R′ is hydrogen or alkyl as indicatedabove, and R is alkyl as indicated above.

The term “alkylsulfonylamino” is intended to indicate a radical of theformula —NR′—S(O)₂—R, wherein R is alkyl as indicated above, and R′ ishydrogen or alkyl as indicated above, e.g. methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino or butylsulfonylamino.

The term “arylsulfonylamino” is intended to indicate a radical of theformula —NR′—S(O)₂—R, wherein R is aryl as indicated above, and R′ ishydrogen, or alkyl as indicated above, e.g. phenylsulfonylamino.

The term “alkoxysulfonyloxy” is intended to represent a radical of theformula —O—S(O)₂—O—R, wherein R is alkyl as indicated above.

The term “arylsulfonylaminocarbonyl” is intended to indicate a radicalof the formula —C(O)—NR′—S(O)₂—R, wherein R is aryl as indicated above,and R′ is hydrogen or alkyl as indicated above, e.g.phenylsulfonylaminocarbonyl.

The term “arylcarbonylamino” is intended to indicate a radical of theformula —NR′—C(O)—R, wherein R′ is hydrogen or alkyl as indicated above,and R is aryl as indicated above e.g. phenylcarbonylamino.

The term “alkenylcarbonylamino” is intended to indicate a radical of theformula —NR′—C(O)—R, wherein R′ is hydrogen or alkyl as indicated above,and R is alkenyl as indicated above.

The term “cycloalkylcarbonylamino” is intended to indicate a radical ofthe formula —NR′—C(O)—R, wherein R′ is hydrogen or alkyl as indicatedabove, and R is cycloalkyl as indicated above.

The term “cycloalkenylcarbonylamino” is intended to indicate a radicalof the formula —NR′—C(O)—R, wherein R′ is hydrogen or alkyl as indicatedabove, and R is cycloalkenyl as indicated above.

The term “heterocycloalkylcarbonylamino” is intended to indicate aradical of the formula —NR′—C(O)—R, wherein R′ is hydrogen or alkyl asindicated above, and R is heterocycloalkyl as indicated above.

The term “ureido” is intended to indicate a radical of the formula“—NR′—C(O)—NH—R, wherein R′ is hydrogen or alkyl as indicated above, andR is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl as indicatedabove.

The term “thioureido” is intended to indicate a radical of the formula“—NR′—C(S)—NH—R, wherein R′ is hydrogen or alkyl as indicated above, andR is hydrogen, alkyl, or cycloalkyl as indicated above.

The term “pharmaceutically acceptable salt” is intended to indicatesalts prepared by reacting a compound of formula I with a suitableinorganic or organic acid, such as hydrochloric, hydrobromic,hydroiodic, sulfuric, nitric, phosphoric, formic, acetic,2,2-dichloroacetic, choline, adipic, ascorbic, L-aspartic, L-glutamic,galactaric, lactic, maleic, L-malic, phthalic, citric, propionic,benzoic, glutaric, gluconic, D-glucuronic, methanesulfonic, salicylic,succinic, malonic, tartaric, benzenesulfonic, ethane-1,2-disulfonic,2-hydroxy ethanesulfonic acid, toluenesulfonic, sulfamic or fumaricacid. Pharmaceutically acceptable salts of compounds of formula I mayalso be prepared by reaction with a suitable base such as sodiumhydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide,ammonia, or suitable non-toxic amines, such as lower alkylamines, forexample triethylamine, hydroxy-lower alkylamines, for example2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine, cycloalkylamines, forexample dicyclohexylamine, or benzylamines, for exampleN,N′-dibenzylethylene-diamine, and dibenzylamine, or L-arginine orL-lysine.

The term “solvate” is intended to indicate a species formed byinteraction between a compound, e.g. a compound of formula I, and asolvent, e.g. alcohol, glycerol or water, wherein said species are in asolid form. When water is the solvent, said species is referred to as ahydrate.

The term “pharmaceutically acceptable in vivo hydrolysable ester” isintended to indicate easily in vivo hydrolysable esters, i.e. in vivohydrolysable esters of the compounds of formula I such asalkanoyloxyalkyl, aralkanoyloxyalkyl, aroyloxyalkyl, e.g. acetoxymethyl,pivaloyloxymethyl, benzoyloxymethyl esters and the corresponding1′-oxyethyl derivatives, or alkoxycarbonyloxyalkyl esters, e.g.methoxycarbonyloxymethyl esters and ethoxycarbonyloxymethyl esters andthe corresponding 1′-oxyethyl derivatives, or lactonyl esters, e.g.phthalidyl esters, or dialkylaminoalkyl esters, e.g. dimethylaminoethylesters. Such esters may be prepared by conventional methods known topersons skilled in the art, such as method disclosed in GB patent No. 1490 852 incorporated herein by reference.

Compounds of formula I may comprise asymmetrically substituted (chiral)carbon atoms and carbon-carbon double bonds which may give rise to theexistence of isomeric forms, e.g. enantiomers, diastereomers andgeometric isomers. The present invention includes all such isomers,either in pure form or as mixtures thereof. Pure stereoisomeric forms ofthe compounds and the intermediates of this invention may be obtained bythe application of procedures known in the art. Diastereomers may beseparated by physical separation methods such as selectivecrystallization and chromatographic techniques, e.g. liquidchromatography using chiral stationary phases. Enantiomers may beseparated from each other by the selective crystallization of theirdiastereomeric salts with optically active acids. Alternatively,enantiomers may be separated by chromatographic techniques using chiralstationary phases. Said pure stereoisomeric forms may also be derivedfrom the corresponding pure stereoisomeric forms of the appropriatestarting materials, provided that the reaction occurs stereoselectivelyor stereospecifically. Preferably, if a specific stereoisomer isdesired, said compound will be synthesized by stereoselective orstereospecific methods of preparation. These methods will advantageouslyemploy chirally pure starting materials. Likewise, pure geometricisomers may be obtained from the corresponding pure geometric isomers ofthe appropriate starting materials. A mixture of geometric isomers willtypically exhibit different physical properties, and they may thus beseparated by standard chromatographic techniques well-known in the art.

The present invention further includes prodrugs of compounds of generalformula I, such as esters, ethers, complexes or other derivatives whichundergo a biotransformation in vivo before exhibiting theirpharmacological effects.

The compounds of formula I may be obtained in crystalline form eitherdirectly by concentration from an organic solvent or by crystallisationor recrystallisation from an organic solvent or mixture of said solventand a cosolvent that may be organic or inorganic, such as water. Thecrystals may be isolated in essentially solvent-free form or as asolvate, such as a hydrate. The invention covers all crystallinemodifications and forms and also mixtures thereof.

EMBODIMENTS

In one embodiment of the present invention, compound I represents:

In one embodiment of the present invention,

represents:

In another embodiment of the present invention R₂ and R₃ representhydrogen.

In another embodiment of the present invention A represents 1-naphthyl.

In another embodiment of the present invention G represents —C(O)—R₆,wherein R₆ represents —NH₂, C₁₋₆amino, hydroxy, mercapto, —C(O)NH₂,trifluoromethyl, carboxy, C₁₋₆alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄hydroxyalkyl, C₁₋₆haloalkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₄aminocarbonyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl,C₁₋₆heterocycloalkenyl, C₃₋₆cycloalkylamino, C₁₋₆heterocycloalkyl,C₁₋₆heterocycloalkylcarbonyl, C₆₋₁₄aryl, C₁₋₆heteroaryl, C₆₋₁₀arylamino,carboxyC₆₋₁₀aryl, C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy,C₁₋₄alkoxysulfonyloxy, C₁₋₄alkylthio, C₁₋₄aminocarbonyloxy,C₁₋₄alkylsulfonylamino, C₁₋₄alkylcarbonylamino,C₁₋₄alkenylcarbonylamino, C₃₋₆cycloalkenylcarbonylamino,C₃₋₆cycloalkylcarbonylamino, C₁₋₄alkoxycarbonylamino,C₆₋₁₀arylcarbonylamino or C₆₋₁₀arylsulfonylamino, wherein saidC₁₋₆amino, C₁₋₆alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄hydroxyalkyl,C₁₋₆haloalkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄aminocarbonyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, C₁₋₆heterocycloalkenyl,C₃₋₆cycloalkylamino, C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkylcarbonyl,C₆₋₁₄aryl, C₁₋₆heteroaryl, C₆₋₁₀arylamino, carboxyC₆₋₁₀aryl,C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy, C₁₋₄alkoxysulfonyloxy,C₁₋₄alkylthio, C₁₋₄aminocarbonyloxy, C₁₋₄alkylsulfonylamino,C₁₋₄alkylcarbonylamino, C₁₋₄alkenylcarbonylamino,C₃₋₆cycloalkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino,C₁₋₄alkoxycarbonylamino, C₆₋₁₀arylcarbonylamino orC₆₋₁₀arylsulfonylamino, may further be optionally substituted with oneor more same or different substituents represented by hydroxy, halogen,C₁₋₄alkyl, C₁₋₃alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₆heterocycloalkyl,C₆₋₁₂aryl or oxo,

wherein said C₁₋₄alkyl, C₁₋₃alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₆heterocycloalkyl or C₆₋₁₂aryl are optionally further substitutedwith trifluoromethyl, halogen, C₁₋₄alkyl, C₁₋₃alkoxy orC₁₋₄alkoxycarbonyl.

In yet another embodiment of the present invention G represents—C(O)NH₂, C₁₋₄aminocarbonyl, C₄₋₅heterocycloalkylcarbonyl,C₆₋₁₀arylaminocarbonyl, C₆₋₁₀arylsulfonylaminocarbonyl,

wherein said C₁₋₄aminocarbonyl, C₄₋₅heterocycloalkylcarbonyl,C₆₋₁₀arylaminocarbonyl or C₆₋₁₀arylsulfonylaminocarbonylare optionally substituted with one or more, same or differentsubstituents selected from oxo, hydroxy, C₁₋₄alkyl, C₁₋₃alkoxy,C₁₋₃alkoxycarbonyl, C₄₋₅heterocycloalkyl, C₆₋₁₀aryl,wherein said C₁₋₄alkyl, C₁₋₃alkoxy, C₁₋₃alkoxycarbonyl,C₄₋₅heterocycloalkyl or C₆₋₁₀aryl are optionally substituted with one ormore, same or different substituents represented by halogen,trifluoromethyl, C₁₋₃alkoxy or C₁₋₃alkoxycarbonyl.

In yet another embodiment of the present invention G representsmethylpiperazinylcarbonyl, cyclopropylaminocarbonyl,isopropylaminocarbonyl, propylaminocarbonyl, morpholinocarbonyl,dimethylaminocarbonyl, isobutylaminocarbonyl, ethylaminocarbonyl,N-methoxy-N-methylaminocarbonyl, methoxycarbonylmethyleneaminocarbonyl,methoxyethyleneaminocarbonyl, ethoxycarbonylphenyleneaminocarbonyl,dimethylmorpholinocarbonyl, morpholinopropylaminocarbonyl,ethoxycarbonylpiperidinocarbonyl, chlorobenzylaminocarbonyl,phenylhydroxyethylaminocarbonyl, ethoxycarbonylethyleneaminocarbonyl,trifluoromethylphenylenepiperazinylcarbonyl,hydroxyindanylaminocarbonyl,phenylmethoxycarbonylmethyleneaminocarbonyl,methoxyethylenepiperazinylcarbonyl, trifluorobenzylaminocarbonyl,methoxycarbonylbenzylaminocarbonyl, methylphenylenesulfonylaminocarbonylor carboxyphenylmethyleneaminocarbonyl.

In yet another embodiment of the present invention G represents phenyloptionally substituted with one or more, same or different substituentsselected from —C(O)H, —C(O)NH₂, hydroxy, halogen, cyano, nitro, amidino,carboxy, trifluoromethyl, C₁₋₆alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄hydroxyalkyl, C₁₋₆amino, aminoC₁₋₃alkyl, iminomethyl,hydroxyiminomethyl, C₁₋₆haloalkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₃alkoxycarbamoyl, C₁₋₄aminocarbonyl, C₁₋₃alkylsulfonylaminocarbonyl,hydroxyaminocarbonyl, C₁₋₆heterocycloalkyloxy,C₁₋₆heterocycloalkylaminocarbonyl, C₃₋₆cycloalkylaminocarbonyl,C₆₋₁₀arylaminocarbonyl, C₁₋₁₀heteroarylaminocarbonyl, C₃₋₆cycloalkyl,C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl,C₁₋₆heterocycloalkylcarbonyl, C₁₋₄alkylcarbonyloxy,C₁₋₄alkoxycarbonyloxy, C₁₋₄alkoxysulfonyloxy, C₁₋₄alkylthio,C₃₋₆cycloalkenyl, C₁₋₄aminosulfonyl, C₁₋₄aminocarbonyloxy,C₁₋₄alkylsulfonylamino, C₁₋₁₀heteroaryl, C₆₋₁₀arylamino,C₆₋₁₀aryloxycarbonyl, C₆₋₁₀arylcarbonylamino, C₆₋₁₀arylsulfonylamino,C₁₋₄alkylcarbonylamino, C₁₋₄alkenylcarbonylamino,C₃₋₆cycloalkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino,C₁₋₄alkoxycarbonylamino, C₁₋₆heterocycloalkylcarbonylamino,C₁₋₄alkylsulfonyl or C₁₋₆heterocycloalkylsulfonyl, wherein said C(O)NH₂,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄hydroxyalkyl, C₁₋₆amino, aminoC₁₋₃alkyl,iminomethyl, hydroxyiminomethyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₃alkoxycarbamoyl, C₁₋₄aminocarbonyl, C₁₋₃alkylsulfonylaminocarbonyl,hydroxyaminocarbonyl, C₁₋₆heterocycloalkyloxy,C₁₋₆heterocycloalkylaminocarbonyl, C₃₋₆cycloalkylaminocarbonyl,C₆₋₁₀arylaminocarbonyl, C₁₋₁₀heteroarylaminocarbonyl, C₃₋₆cycloalkyl,C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl,C₁₋₆heterocycloalkylcarbonyl, C₁₋₄alkylcarbonyloxy,C₁₋₄alkoxycarbonyloxy, C₁₋₄alkoxysulfonyloxy, C₁₋₄alkylthio,C₃₋₆cycloalkenyl, C₁₋₄aminosulfonyl, C₁₋₄aminocarbonyloxy,C₁₋₄alkylsulfonylamino, C₁₋₁₀heteroaryl, C₆₋₁₀arylamino,C₆₋₁₀aryloxycarbonyl, C₆₋₁₀arylcarbonylamino, C₆₋₁₀arylsulfonylamino,C₁₋₄alkylcarbonylamino, C₁₋₄alkenylcarbonylamino,C₃₋₆cycloalkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino,C₁₋₄alkoxycarbonylamino, C₁₋₆heterocycloalkylcarbonylamino,C₁₋₄alkylsulfonyl, or C₁₋₆heterocycloalkylsulfonyl are optionallyfurther substituted with one or more, same or different substituentsselected from the group consisting of hydroxy, —NH₂, C₁₋₆amino,iminomethyl, hydroxyiminomethyl, carboxy, trifluoromethyl, halogen, oxo,mercapto, cyano, —C(O)NH₂, nitro, C₁₋₆alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄hydroxyalkyl, C₁₋₃alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₆heterocycloalkylcarbonyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl,C₁₋₆heterocycloalkyl, C₆₋₁₂aryl, C₁₋₁₀heteroaryl, C₁₋₃alkoxyC₆₋₁₀aryl,C₁₋₁₀heterocycloalkylaryl, C₁₋₆heterocycloalkenyl, —S(O)₂NH₂, —S(O)₂OH,C₁₋₆ureido, C₁₋₆thioureido, C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy,C₁₋₄alkoxysulfonyloxy, C₁₋₄alkoxycarbamoyl, C₁₋₄aminocarbonyl,C₁₋₄alkylthio, C₁₋₄aminosulfonyl, C₁₋₄aminocarbonyloxy,C₁₋₄alkylsulfonylamino, C₆₋₁₂arylsulfonyl, C₆₋₁₀arylsulfonylamino,C₁₋₄alkylcarbonylamino or C₁₋₄alkylsulfonyl,

wherein said C₃₋₆cycloalkyl, C₁₋₆alkyl, C₁₋₃alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₆heterocycloalkyl, C₆₋₁₀aryl or C₁₋₁₀heteroaryl may be furthersubstituted with carboxy, halogen, hydroxy, cyano, C₁₋₆heterocycloalkyl,one or more C₁₋₆alkyl, C₁₋₃alkoxy, C₁₋₃alkoxyC₁₋₃alkoxyC₁₋₄alkoxycarbonyl, C₁₋₃hydroxyalkyl or C₆₋₁₀aryl.

In yet another embodiment of the present invention G represents phenylsubstituted with one or more same or different substituents selectedfrom cyano, carboxy, —C(O)H, —C(O)NH₂, hydroxyl, halogen, amidino,iminomethyl, hydroxyiminomethyl, C₁₋₆alkyl, C₂₋₄alkynyl, aminoC₁₋₃alkyl,C₁₋₃alkoxy, C₁₋₃alkoxycarbonyl, C₁₋₄alkoxycarbamoyl, C₁₋₃aminocarbonyl,C₃₋₆cycloalkyl, C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkylcarbonyl,C₁₋₆heterocycloalkyloxy, C₁₋₃aminocarbonyloxy, C₁₋₁₀heteroaryl,C₆₋₁₀arylamino, C₆₋₁₀aryloxycarbonyl, C₁₋₃alkylsulfonylaminocarbonyl,hydroxyaminocarbonyl, C₁₋₃alkylsulfonyl, C₁₋₆heterocycloalkylsulfonyl,C₁₋₆heterocycloalkylaminocarbonyl, C₃₋₆cycloalkylaminocarbonyl,C₆₋₁₀arylaminocarbonyl, C₁₋₃aminosulfonyl, C₁₋₁₀heteroarylaminocarbonyl,C₁₋₃alkylcarbonylamino, C₁₋₃alkylsulfonylamino orC₆₋₁₀arylsulfonylamino,

each of which is optionally substituted with one or more same ordifferent substituents selected from hydroxy, —NH₂, C₁₋₃amino,iminomethyl, carboxy, trifluoromethyl, cyano, fluoro, chloro, iodo, oxo,mercapto, C₁₋₄alkyl, C₁₋₃hydroxyalkyl, C₁₋₂alkoxy, C₁₋₄alkoxycarbonyl,C₃₋₆cycloalkyl, C₃₋₅heterocycloalkyl, C₁₋₆heterocycloalkylcarbonyl,C₆₋₁₀aryl, C₁₋₁₀heteroaryl, C₁₋₂alkoxyC₆₋₁₀aryl, C₁₋₃alkylsulfonylamino,—S(O)₂OH or C₁₋₃alkylcarbonylamino,wherein said C₃₋₆cycloalkyl, C₁₋₄alkyl, C₁₋₂alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₆heterocycloalkyl, C₆₋₁₀aryl or C₁₋₁₀heteroaryl are optionallyfurther substituted with carboxy, halogen, hydroxy, cyano,C₁₋₆heterocycloalkyl, one or more C₁₋₆alkyl, C₁₋₃alkoxy,C₁₋₃alkoxyC₁₋₃alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₃hydroxyalkyl or C₆₋₁₀aryl,such as hydroxymethylpyrrolidinylcarbonyl, ethylaminocarbonyl,dimethylaminoethylmethylaminocarbonyl, pyrrolidinyliminomethyl, amidino,aminohydroxyiminomethyl, methoxycarbonyl, ethoxycarbonyl,hydroxyethylaminocarbonyl, N-hydroxyethyl-N-methylaminocarbonyl,N-hydroxymethyl-N-propylaminocarbonyl, bishydroxyethylaminocarbonyl,dihydroxytert-butylaminocarbonyl, N-hydroxyethyl-N-ethylaminocarbonyl,cyanoethylaminocarbonyl, morpholinoethylaminocarbonyl,fluoroethylaminocarbonyl, difluoroethylaminocarbonyl,methoxycarbonylethylaminocarbonyl,N-pyridylmethyl-N-methylaminocarbonyl, benzyloxycarbamoyl,methylcarbonylaminoethylaminocarbonyl, iodophenyleneoxycarbonyl,methoxyethylaminocarbonyl, mercaptoethylaminocarbonyl,ethoxycarbonylmethylaminocarbonyl, sulfoethylaminocarbonyl,dimethylaminocarbonyl, dimethylaminoethylaminocarbonyl,dimethylaminopropylaminocarbonyl, piperidinocarbonyl,methylpiperazinylcarbonyl, hydroxyethylpiperazinylcarbonyl,morpholinocarbonyl, hydroxypiperidinocarbonyl,imidazolylpropylaminocarbonyl, carboxymethylaminocarbonyl,tert-butoxycabonylmethoxycarbonylethylaminocarbonyl,tert-butoxycarbonylcarboxyethylaminocarbonyl,methoxycarbonylphenylethylaminocarbonyl,carboxyphenylethylaminocarbonyl,methoxycarbonylindolylethylaminocarbonyl,carboxyindolylethylaminocarbonyl,N-ethoxycarbonylmethyl-N-cyclohexylaminocarbonyl,diethoxycarbonylmethylaminocarbonyl,tert-butoxycarbonylhydroxyethylaminocarbonyl,carboxypyridylaminocarbonyl, carboxyphenylaminocarbonyl,methoxyethoxycarbonylphenylaminocarbonyl,N,N-dicarboxymethylaminocarbonyl, carboxycyclopentylmethylaminocarbonyl,carboxyethylaminocarbonyl, carboxymethylcyclohexylaminocarbonyl,ethylcarboxycyclopropylaminocarbonyl, carboxycyclopropylaminocarbonyl,carboxyisopropylaminocarbonyl, carboxyazetidinylcarbonyl,N-methyl-N-carboxymethylaminocarbonyl, carboxypropylaminocarbonyl,ethoxycarbonylpiperidylcarbocyl, carboxypiperidylcarbonyl,N-carboxymethyl-N-cyclohexylaminocarbonyl,oxotetrahydrofurylaminocarbonyl, cyanomethylaminocarbonyl,cyanopyrazolaminocarbonyl,phenylmethoxycarbonylhydroxyethylaminocarbonyl,methoxycarbonylhydroxyethylaminocarbonyl,ethoxycarbonylhydroxyethylaminocarbonyl,carboxyhydroxyethylaminocarbonyl, carboxyhydroxypropylaminocarbonyl,tert-butoxyaminocarbonyl, methoxyaminocarbonyl,tetrahydrofurylmethoxyaminocarbonyl, N-methoxy-N-methylaminocarbonyl,phenylmethoxyaminocarbonyl, hydroxyaminocarbonyl,morpholinocarbonylmethoxyaminocarbonyl, methylsulfonylaminocarbonyl,methoxycarbonylhydroxypyrrolidinylcarbonyl,carboxyhydroxypyrrolidinylcarbonyl, ethoxycarbonylmethoxy,methoxycarbonylethyl, carboxymethoxy or carboxyethyl.

In one embodiment when G represents phenyl being further substituted thesubstituent is attached to the phenylene ring in the meta or paraposition from where the phenyl ring is attached to the cycloalkylrepresenting

In another embodiment when G represents phenyl being furthersubstituted, the substituent is attached to the phenylene ring in theortho position from where the phenyl ring is attached to the cycloalkylrepresenting

In yet another embodiment of the present invention G representsC₁₋₁₀heteroaryl or C₁₋₆heterocycloalkyl and wherein said C₁₋₁₀heteroarylor C₁₋₆heterocycloalkyl is optionally substituted with carboxy,C₁₋₆alkyl, C₆₋₁₀aryl, C₁₋₃alkoxycarbonyl, which may further beoptionally substituted with trifluoromethyl, halogen, C₁₋₃alkyl,C₁₋₃alkoxy, C₁₋₁₀heteroaryl, wherein C₁₋₁₀heteroaryl may further besubstituted with C₁₋₃alkyl or oxo, such asfluorophenylene[1,2,4]oxadiazolyl, phenyl[1,2,4]oxadiazolyl,isopropyl[1,2,4]oxadiazolyl, trifluoromethylphenylene[1,2,4]oxadiazolyl,methyl[1,2,4]oxadiazolyl, methylthiazolylmethylene[1,2,4]oxadiazolyl,propyl[1,2,4]oxadiazolyl, oxopyridinylmethylene[1,2,4]oxadiazolyl,methoxyphenylene[1,2,4]oxadiazolyl, methylcarboxylmidazolyl,ethoxycarbonylthienyl, ethoxycarbonylfuryl, pyridyl, carboxythienyl orcarboxyfuryl.

In yet another embodiment of the present invention G representsphenylamino or phenyloxy, optionally substituted with cyano, carboxy,C₁₋₄alkoxycarbonyl or trifluoromethyl.

In yet another embodiment of the present invention A represents1-naphthyl, 2-naphthyl or phenyl, each of which is optionallysubstituted as defined above for the substitution of C₆₋₁₄arylrepresenting A.

In yet another embodiment of the present invention R₄ representshydrogen, hydroxy, halogen or C₁₋₆alkyl.

In yet another embodiment of the present invention R₅ representshydrogen or C₁₋₆alkyl.

In yet another embodiment of the present invention R₂, R₃, R₄ and R₅represent hydrogen.

In yet another embodiment of the present invention R₁ represents methyl,ethyl or n-propyl, optionally substituted with halogen or hydroxy, suchas methyl.

In yet another embodiment, the present invention relates to compounds ofgeneral formula I, wherein G represents C₆₋₁₀aryl,C₁₋₃aminocarbonylC₆₋₁₀aryl or C₁₋₄alkylC₆₋₁₀aryl optionally substitutedwith carboxy, C₁₋₃alkoxy or C₁₋₃alkoxycarbonyl, A represents 1-naphthyl,R₂, R₃, R₄ and R₅ represent hydrogen and R₁ represents methyl.

Specific examples of compounds of formula I may be selected from thegroup consisting of

-   3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    (compound 1000),-   cyclobutyl-((R)-1-naphthalen-1-yl-ethyl)-amine, hydrochloride    (compound 1001),-   3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    dimethylamide (compound 1002),-   3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    amide (compound 1003),-   (4-Methyl-piperazin-1-yl)-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutyl]-methanone;    hydrochloride (compound 1004),-   3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    cyclopropylamide (compound 1005),-   3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    isopropylamide (compound 1006),-   3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    propylamide (compound 1007),-   Morpholin-4-yl-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutyl]-methanone    (compound 1008),-   3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    tert-butylamide (compound 1009),-   3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    ethylamide (compound 1010),-   3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    methoxy-methyl-amide; hydrochloride (compound 1011),-   [3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclobutyl]-((R)-1-naphthalen-1-yl-ethyl)-amine;    hydrochloride (compound 1012),-   ((R)-1-Naphthalen-1-yl-ethyl)-{3-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclobutyl}-amine;    hydrochloride (compound 1013),-   [3-(3-Methyl-[1,2,4]oxadiazol-5-yl)-cyclobutyl]-((R)-1-naphthalen-1-yl-ethyl)-amine;    hydrochloride (compound 1014),-   ((R)-1-Naphthalen-1-yl-ethyl)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-cyclobutyl]-amine;    hydrochloride (compound 1015),-   ((R)-1-Naphthalen-1-yl-ethyl)-{3-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclobutyl}-amine;    hydrochloride (compound 1016),-   {3-(3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclobutyl}-((R)-1-naphthalen-1-yl-ethyl)-amine;    hydrochloride (compound 1017),-   3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    4-chloro-benzylamide (compound 1018),-   {[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-acetic    acid methyl ester (compound 1019),-   3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    (2-methoxy-ethyl)-amide (compound 1020),-   4-{[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-benzoic    acid ethyl ester (compound 1021),-   (2,6-Dimethyl-morpholin-4-yl)-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutyl]-methanone    (compound 1022),-   3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    (3-morpholin-4-yl-propyl)-amide (compound 1023),-   1-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-piperidine-4-carboxylic    acid ethyl ester (compound 1024),-   3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    (2-hydroxy-2-phenyl-ethyl)-amide (compound 1025),-   3-{[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-propionic    acid ethyl ester (compound 1026),-   [3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutyl]-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone    (compound 1027),-   {[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-phenyl-acetic    acid methyl ester (compound 1028),-   3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    (2-hydroxy-indan-1-yl)-amide (compound 1029),-   [4-(2-Methoxy-ethyl)-piperazin-1-yl]-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutyl]-methanone    (compound 1030),-   3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid    2,3,6-trifluoro-benzylamide (compound 1031),-   3-({[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-methyl)-benzoic    acid methyl ester (compound 1032),-   4-({[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-methyl)-benzoic    acid methyl ester (compound 1033),-   {[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-phenyl-acetic    acid (compound 1034),-   ((R)-1-Naphthalen-1-yl-ethyl)-(3-phenyl-cyclobutyl)-amine (compound    1035 and compound 1036),-   {3-[3-(4-Fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopentyl}-((R)-1-naphthalen-1-yl-ethyl)-amine;    hydrochloride (compound 1037),-   ((R)-1-Naphthalen-1-yl-ethyl)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-cyclopentyl]-amine;    hydrochloride (compound 1038),-   [3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclopentyl]-(R)-1-naphthalen-1-yl-ethyl)-amine;    hydrochloride (compound 1039),-   ((R)-1-Naphthalen-1-yl-ethyl)-{3-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopentyl}-amine;    hydrochloride (compound 1040),-   [3-(3-Methyl-[1,2,4]oxadiazol-5-yl)-cyclopentyl]-((R)-1-naphthalen-1-yl-ethyl)-amine;    hydrochloride (compound 1041),-   {3-[3-(5-Methyl-thiazol-2-ylmethyl)-[1,2,4]oxadiazol-5-yl]-cyclopentyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1042),-   ((R)-1-naphthalen-1-yl-ethyl)-[3-(3-propyl-[1,2,4]oxadiazol-5-yl)-cyclopentyl]-amine;    hydrochloride (compound 1043a and 1043b),-   1-{5-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-[1,2,4]oxadiazol-3-ylmethyl}-1H-pyridin-2-one;    hydrochloride (compound 1044),-   {3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopentyl}-((R)-1-naphthalen-1-yl-ethyl)-amine;    hydrochloride (compound 1045),-   3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid    amide (compound 1046),-   4-Methyl-N-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentane    carbonyl]-benzenesulfonamide (compound 1047a, compound 1047b,    compound 1047c and compound 1047d),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzonitrile    (compounds 1048/1049/1050),-   N-Hydroxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamidine    (compound 1051),-   N-Hydroxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamidine    (compound 1052),-   N-Hydroxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamidine    (compound 1053a and compound 1053b),-   {3-[4-(Imino-pyrrolidin-1-yl-methyl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1054),-   4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamidine    (compound 1055),-   4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    (compound 1056),-   4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    (compound 1057),-   4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    (compound 1058, 1058a),-   3-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    ethyl ester (compound 1059),-   N-(2-Hydroxy-ethyl)-3-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1060),-   3-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    (compounds 1061/1062),-   ((R)-1-Naphthalen-1-yl-ethyl)-(3 (S)-phenyl-cyclohexyl)-amine    (compound 1063),-   ((R)-1-Naphthalen-1-yl-ethyl)-(3 (R)-phenyl-cyclohexyl)-amine    (compound 1064),-   N—((R)-1-Naphthalen-1-yl-ethyl)-N′-phenyl-cyclohexane-1,3-diamine    (compound 1065),-   N—((R)-1-Naphthalen-1-yl-ethyl)-N′-(3-trifluoromethyl-phenyl)-cyclohexane-1,3-diamine    (compound 1066),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexylamino]-benzonitrile    (compound 1067),-   (3-Morpholin-4-yl-cyclohexyl)-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1068),-   ((R)-1-Naphthalen-1-yl-ethyl)-(3-pyridin-2-yl-cyclohexyl)-amine    (compounds 1069/1070),-   5-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-thiophene-2-carboxylic    acid ethyl ester (compound 1071),-   5-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-thiophene-2-carboxylic    acid (compound 1072),-   5-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-furan-2-carboxylic    acid ethyl ester (compound 1073),-   5-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-furan-2-carboxylic    acid (compound 1074a, compound 1074b and compound 1074c),-   {3-[3-(4-Fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1075),-   ((R)-1-Naphthalen-1-yl-ethyl)-{3-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclohexyl}-amine    (compound 1076),-   ((R)-1-Naphthalen-1-yl-ethyl)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-amine    (compound 1077),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1078),-   N-Benzyloxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1079),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    4-iodo-phenyl ester (compound 1080),-   2-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-ethanesulfonic    acid (compound 1081),-   N—((R)-1-Hydroxymethyl-propyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1082),-   N—((S)-1-Hydroxymethyl-propyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1083),-   N-(2-Cyano-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1084),-   N-(2-Morpholin-4-yl-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1085),-   N-(2-Fluoro-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1086),-   N-(2,2-Difluoro-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1087),-   3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid methyl ester (compound 1088),-   N-Methyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-N-pyridin-4-ylmethyl-benzamide    (compound 1089),-   N-(2-Dimethylamino-ethyl)-N-methyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1090),-   (2-Hydroxymethyl-pyrrolidin-1-yl)-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone    (compound 1091),-   N-(2-Acetylamino-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1092),-   N-Ethyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1093),-   N-(2-Hydroxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1094),-   N-(2-Hydroxy-1-hydroxymethyl-1-methyl-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1095),-   N-(2-Methoxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1096),-   N-(2-Mercapto-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1097),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-acetic    acid ethyl ester (compound 1098),-   N,N-Dimethyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1099),-   N-(2-Hydroxy-ethyl)-N-methyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1100),-   N-Ethyl-N-(2-hydroxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1101),-   N,N-Bis-(2-hydroxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1102),-   N-(2-Dimethylamino-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1103),-   N-(3-Dimethylamino-propyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1104),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-piperidin-1-yl-methanone    (compound 1105),-   (4-Methyl-piperazin-1-yl)-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone    (compound 1106),-   [4-(2-Hydroxy-ethyl)-piperazin-1-yl]-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone    (compound 1107),-   Morpholin-4-yl-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone    (compound 1108),-   (4-Hydroxy-piperidin-1-yl)-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone    (compound 1109),-   N-(3-Imidazol-1-yl-propyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1110),-   3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid    (compound 1111),-   {4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-acetic    acid (compound 1115),-   (S)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-succinic    acid 4-tert-butyl ester 1-methyl ester (compound 1116),-   (S)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-succinic    acid 4-tert-butyl ester (compound 1117),-   (R)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionic    acid methyl ester (compound 1118),-   (R)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionic    acid (compound 1119),-   (S)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionic    acid methyl ester (compound 1120),-   (S)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionic    acid; hydrochloride (compound 1121),-   (S)-3-(1H-Indol-3-yl)-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid methyl ester (compound 1122),-   (S)-3-(1H-Indol-3-yl)-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid (compound 1123),-   (R)-3-(1H-Indol-3-yl)-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid methyl ester (compound 1124),-   (R)-3-(1H-Indol-3-yl)-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid (compound 1125),-   (Cyclohexyl-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-acetic    acid ethyl ester (compound 1126),-   2-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-malonic    acid diethyl ester (compound 1127),-   (S)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid tert-butyl ester (compound 1128),-   5-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-nicotinic    acid (compound 1129),-   4-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-benzoic    acid (compound 1130),-   4-Methoxy-3-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-benzoic    acid methyl ester; hydrochloride (compound 1131),-   2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-benzoic    acid; hydrochloride (compound 1132),-   (Carboxymethyl-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-acetic    acid; hydrochloride (compound 1133),-   1-({4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-methyl)-cyclopentanecarboxylic    acid (compound 1134),-   1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-cyclopentanecarboxylic    acid; hydrochloride (compound 1135),-   3-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid; hydrochloride (compound 1136),-   (1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-cyclohexyl)-acetic    acid; hydrochloride (compound 1137),-   1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-cyclopropanecarboxylic    acid ethyl ester (compound 1138),-   1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-cyclopropanecarboxylic    acid (compound 1139),-   1-({4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-methyl)-cyclopropanecarboxylic    acid (compound 1140),-   2-Methyl-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid (compound 1141),-   1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-azetidine-3-carboxylic    acid (compound 1142),-   (Methyl-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-acetic    acid (compound 1143),-   4-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-butyric    acid (compound 1144),-   1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-piperidine-4-carboxylic    acid ethyl ester (compound 1145),-   1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-piperidine-4-carboxylic    acid (compound 1146),-   (Cyclohexyl-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-acetic    acid ethyl ester (compound 1147),-   (Cyclohexyl-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-acetic    acid (compound 1148),-   4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-N—((R)-2-oxo-tetrahydro-furan-3-yl)-benzamide    (compound 1149),-   N-Cyanomethyl-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1150),-   N-(4-Cyano-1H-pyrazol-3-yl)-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1151),-   (R)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid benzyl ester (compound 1152),-   (S)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid benzyl ester (compound 1153),-   (S)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid methyl ester (compound 1154),-   (R)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid methyl ester (compound 1155),-   (S)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid ethyl ester; hydrochloride (compound 1156),-   3-Hydroxy-2-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic    acid; hydrochloride (compound 1157),-   (R)-4-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-butyric    acid (compound 1158),-   N-tert-Butoxy-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide;    formiate (compound 1159),-   N-tert-Butoxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide;    formiate (compound 1160),-   N-Methoxy-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide;    formiate (compound 1161),-   N-Methoxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide;    formiate (compound 1162),-   4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-N-(tetrahydro-furan-3-ylmethoxy)-benzamide    (compound 1163),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-N-(tetrahydro-furan-3-ylmethoxy)-benzamide    (compound 1164),-   N-Methoxy-N-methyl-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide;    bis formate (compound 1165),-   N-Methoxy-N-methyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1166),-   N-Benzyloxy-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1167),-   N-Benzyloxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1168),-   N-Hydroxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1169),-   N-Hydroxy-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1170),-   N-(2-Morpholin-4-yl-2-oxo-ethoxy)-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1171),-   N-(2-Morpholin-4-yl-2-oxo-ethoxy)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide    (compound 1172),-   N-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-methanesulfonamide    (compound 1173),-   4R-Hydroxy-1-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-pyrrolidine-2S-carboxylic    acid methyl ester (compound 1174),-   4R-Hydroxy-1-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-pyrrolidine-2S-carboxylic    acid (compound 1175),-   N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-methanesulfonamide;    hydrochloride (compound 1176),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic    acid ethyl ester (compound 1177/1178),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic    acid ethyl ester (compound 1179/1180),-   3-{4-[(3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid methyl ester (compounds 1181/1182/1183/1184),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic    acid (compound 1185),    {4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic    acid (compound 1186),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic    acid (compound 1187),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic    acid (compound 1188),-   3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid (compound 1189),-   3-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid; hydrochloride (compound 1190),-   3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid (compound 1191),-   3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid (compound 1192),-   {3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic    acid ethyl ester (compounds 1193/1194/1195/1196),-   3-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid ethyl ester (compounds 1197/1198/1198/1200),-   {3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic    acid hydrochloride (compound 1201),-   {3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic    acid (compound 1202),-   {3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic    acid (compound 1203),-   3-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid hydrochloride (compound 1204),-   3-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid (compound 1205),-   3-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid (compound 1206),-   3-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid (compound 1207),-   3-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid hydrochloride (compound 1208),-   [3-(4-Iodo-phenyl)-cyclohexyl]-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1209),-   1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-pyrrolidin-2-one    (compound 1210),-   3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-oxazolidin-2-one    (compound 1211),-   N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-acetamide    (compound 1212),-   4-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-tetrahydro-pyran-4-ol    (compound 1213),-   [3-(4-Imidazol-1-yl-phenyl)-cyclohexyl]-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1214),-   1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-cyclopentanol    (compound 1215),-   1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-ethanone    (compound 1216),-   4-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-tetrahydro-pyran-4-ol    hydrochloride (compound 1217),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanol    (compound 1218),-   1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-cyclobutanol    (compound 1219),-   2-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-malonic    acid diethyl ester (compound 1220),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-acetic    acid ethyl ester (compound 1221),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-acetic    acid (compound 1222),-   3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-oxetan-3-ol    (compound 1223),-   {3-[4-(3-Fluoro-oxetan-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1224),-   {3-[4-(3-Amino-3-methyl-but-1-ynyl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1225),-   {3-[4-(5-Cyclopropyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1226),-   {3-[4-(5-Cyclopentyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1227),-   {3-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1228),-   {3-[4-(5-Isopropyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1229),-   {3-[4-(5-tert-Butyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1230),-   {3-[4-(5-Cyclohexyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1231),-   (3-{4-[5-(3-Methyl-butyl)-[1,2,4]oxadiazol-3-yl]-phenyl}-cyclohexyl)-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1232),-   5-(3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-[1,2,4]oxadiazol-5-ylmethyl)-imidazolidine-2,4-dione    (compound 1233),-   (3-{4-[5-(4-Methyl-oxazol-5-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-cyclohexyl)-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1234),-   (3-{4-[5-(2,5-Dimethyl-oxazol-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-cyclohexyl)-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1235),-   2-Methyl-2-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-propionitrile    (compound 1236/1237),-   2-Methyl-2-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-propionic    acid (compound 1238),-   2-Methyl-2-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-propionic    acid (compound 1239),-   [3-(4-Methanesulfonyl-phenyl)-cyclohexyl]-((R)-1-naphthalen-1-yl-ethyl)-amine    (compounds 1240),-   2-Fluoro-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic    acid methyl ester (compound 1241),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanol    (compound 1242),-   N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-methanesulfonamide    (compound 1243),-   {3-[4-(Morpholine-4-sulfonyl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1244/1245),-   N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-acetamide    (compounds 1246/1247),-   3-Fluoro-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic    acid methyl ester (compound 1248),-   N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanesulfonamide    (compound 1249/1250),-   N-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanesulfonamide    (compound 1251),-   N-(2-Hydroxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzenesulfonamide    (compounds 1252/1253),-   3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-propionic    acid (compound 1254),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenoxy}-acetic    acid (compound 1255),-   [3-(4-Methanesulfonyl-phenyl)-cyclopentyl]-((R)-1-naphthalen-1-yl-ethyl)-amine    (compounds 1256/1257),-   N-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-methanesulfonamide    (compounds 1258/1259),-   N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-acetamide    (compounds 1260/1261),-   N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzyl}-acetamide    (compound 1262/1263),-   N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzyl}-methanesulfonamide    (compounds 1264/1265),-   N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-methanesulfonamide    (compounds 1266/1267),-   [3-(4-Methanesulfonyl-phenyl)-cycloheptyl]-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1268),-   2-Fluoro-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cycloheptyl]-benzoic    acid methyl ester (compound 1269),-   N-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-methanesulfonamide    (compound 1270),-   N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-acetamide    (compound 1271/1272),-   N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-benzyl}-acetamide    (compounds 1273/1274),-   N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-benzyl}-methanesulfonamide    (compounds 1275/1276),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenoxy}-acetic    acid ethyl ester (compound 1277),-   3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-propionic    acid methyl ester (compounds 1278/1279),-   N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-methanesulfonamide    (compounds 1280/1281),-   {3-[4-(Morpholine-4-sulfonyl)-phenyl]-cycloheptyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1282),-   {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-methanol    (compound 1283),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    methyl ester (compound 1284),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    ethyl ester (compound 1285),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    2-morpholin-4-yl-ethyl ester dihydrochloride (compound 1286),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    2-(2-methoxy-ethoxy)-ethyl ester hydrochloride (compound 1287),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester hydrochloride (compound    1288),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    2-[2-(2-ethoxy-ethoxy)-ethoxy]-ethyl ester hydrochloride (compound    1289),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    2,3-dihydroxy-propyl ester hydrochloride (compound 1290),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid    tetrahydro-furan-2-ylmethyl ester hydrochloride (compound 1291),-   4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenol    (compound 1292),-   2-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-butyric    acid ethyl ester (compound 1293),-   2-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-butyric    acid (compound 1294),-   2-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propionic    acid (compound 1295),-   3-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-dihydro-furan-2-one    (compound 1296),-   (S)-{3R-[4-(2-Ethoxy-ethoxy)-phenyl]-cyclopentyl}-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1297),-   3-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propionic    acid ethyl ester (compound 1298),-   4-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxymethyl}-benzonitrile    (compound 1299),-   (S)—((R)-1-Naphthalen-1-yl-ethyl)-{3R-[4-(pyridin-3-ylmethoxy)-phenyl]-cyclopentyl}-amine    (compound 1300),-   (S)—((R)-1-Naphthalen-1-yl-ethyl)-{3R-[4-(2-pyrazol-1-yl-ethoxy)-phenyl]-cyclopentyl}-amine    (compound 1301),-   (S)-(3R-{4-[2-(1H-Indol-3-yl)-ethoxy]-phenyl}-cyclopentyl)-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1302),-   2-Methyl-2-{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propionic    acid hydrochloride (compound 1303),-   4-Hydroxy-2-{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]phenoxy}-butyric    acid (compound 1304),-   2-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propionic    acid hydrochloride (compound 1305),-   {4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-phenyl-acetic    acid hydrochloride (compound 1306),-   2-Methyl-1-{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propan-2-ol    (compound 1307),-   3-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxymethyl}-pentan-3-ol    (compound 1308),-   Dimethyl-carbamic acid    4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl    ester (compound 1309),-   3-Ethyl-1-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-pentan-3-ol    (compound 1310),-   2-Methyl-4-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-butan-2-ol    (compound 1311),-   3-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propane-1,2-diol    (compound 1312),-   (2-Fluoro-phenyl)-{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic    acid hydrochloride (compound 1313),-   2-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-ethanol    formiate (compound 1314),-   (1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-pyrrolidin-2-yl)-methanol    (compound 1315),-   1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-pyrrolidin-3-ol    (compound 1316),-   1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-piperidine-3-carboxylic    acid ethyl ester (compound 1317),-   [3-(4-{[Methyl-(tetrahydro-furan-2-ylmethyl)-amino]-methyl}-phenyl)-cyclohexyl]-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1318),-   3-(4-{(1S,3S)-3-[(R)-1-(4-Fluoro-3-methoxy-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionic    acid ethyl ester (compound 1319),-   3-(4-{(1S,3S)-3-[(R)-1-(3-Cyano-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionic    acid ethyl ester (compound 1320),-   3-{4-[(1S,3S)-3-((R)-1-Benzo[b]thiophen-3-yl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid ethyl ester (compound 1321),-   3-(4-{(1S,3S)-3-[(R)-1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-cyclopentyl}-phenyl)-propionic    acid ethyl ester (compound 1322),-   3-{4-[(1S,3S)-3-((R)-1-Phenyl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid ethyl ester (compound 1323),-   3-(4-{(1S,3S)-3-[(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-cyclopentyl}-phenyl)-propionic    acid ethyl ester (compound 1324),-   3-(4-{(1S,3S)-3-[(R)-1-(1H-Indol-7-yl)-ethylamino]-cyclopentyl}-phenyl)-propionic    acid hydroformiate (compound 1325),-   3-(4-{(1S,3S)-3-[(R)-1-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-ethylamino]-cyclopentyl}-phenyl)-propionic    acid hydroformiate (compound 1326),-   3-(4-{(1S,3S)-3-[(R)-1-(1H-Indol-4-yl)-ethylamino]-cyclopentyl}-phenyl)-propionic    acid hydroformiate (compound 1327),-   3-(4-{(1S,3S)-3-[(R)-1-(3-Cyano-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionic    acid, hydroformiate (compound 1328),-   3-(4-{(1S,3S)-3-[(R)-1-(3-Pyrrolidin-1-yl-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionic    acid hydroformiate (compound 1329),-   3-(4-{(1S,3S)-3-[(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-cyclopentyl}-phenyl)-propionic    acid hydroformiate (compound 1330),-   3-(4-{(1S,3S)-3-[(R)-1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-cyclopentyl}-phenyl)-propionic    acid (compound 1331),-   3-(4-{(1S,3S)-3-[(R)-1-(4-fluoro-3-methoxy-1-yl-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionic    acid (compound 1332),-   3-{4-[(1S,3S)-3-((R)-1-Benzo[b]thiophen-3-yl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid, hydrochloride (compound 1333),-   3-{4-[(1S,3S)-3-((R)-1-Phenyl-ethylamino)-cyclopentyl]-phenyl}-propionic    acid (compound 1334),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoic acid    ethyl ester (compound 1335/1336),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoic acid    (compound 1337),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoic add    (compound 1338),-   3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoylamino}-propionic    acid methyl ester (compound 1339),-   1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoyl}-piperidine-4-carboxylic    acid hydrochloride (compound 1340),-   3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoylamino}-propionic    acid hydrochloride (compound 1341),-   4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyloxy]-benzoic acid    methyl ester (compound 1342),-   4-[3R—((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyloxy]-benzoic    acid formiate (compound 1343),-   5-Methyl-3-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-3H-imidazole-4-carboxylic    acid (compound 1344),-   (3S,4S-Diphenyl-cyclopentyl)-((R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1345),-   5-(4-ethoxy-phenyl)-2-propyl-cyclohexyl]-(R)-1-naphthalen-1-yl-ethyl)-amine    (compound 1346)-   [2-(4-Fluoro-phenyl)-5-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-acetic    acid hydrochloride (compound 1347), or-   3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propan-1-ol    (compound 1348).

Specific examples of intermediates for the preparation of compounds offormula I may be selected from the group consisting of

-   3-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclobutanone    (compound 1112),-   4-methyl-N-(3-oxo-cyclopentanecarbonyl)-benzenesulfonamide (compound    1113),-   3-(3-trifluoromethylphenyl)amino-cyclohexanone (compound 1114),-   3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexanecarboxylic acid    (preparation 4),-   3-(4-Iodophenyl)-cyclohexan-1-one (preparation 5),-   4-(3-Oxo-cyclohexyl)-benzaldehyde (preparation 7),-   3-[4-((1S)-3-Oxo-cyclopentyl)-phenyl]-propionic acid ethyl ester    (preparation 8),-   3-[4-((1S,3R)-3-Acetoxy-cyclopentyl)-phenyl]-propionic acid ethyl    ester (preparation 9),-   3-[4-((1S,3R)-3-Hydroxy-cyclopentyl)-phenyl]-propionic acid ethyl    ester (preparation 10),-   3-[4-((1S,3R)-3-Methanesulfonyloxy-cyclopentyl)-phenyl]-propionic    acid ethyl ester (preparation 11),-   4-((1S,4S)-4-Acetoxy-cyclopent-2-enyloxy)-benzoic acid methyl ester    (preparation 13),-   4-((1S,4S)-4-Hydroxy-cyclopent-2-enyloxy)-benzoic acid methyl ester    (preparation 14),-   4-((1S,4R)-4-Chloro-cyclopent-2-enyloxy)-benzoic acid methyl ester    (preparation 15),-   4-[(1S,4S)-4-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopent-2-enyloxy]-benzoic    acid methyl ester (preparation 16),-   3-((1S,4S)-4-Acetoxy-cyclopent-2-enyl)-5-methyl-3H-imidazole-4-carboxylic    acid ethyl ester (preparation 17),-   3-((1S,4S)-4-Hydroxy-cyclopent-2-enyl)-5-methyl-3H-imidazole-4-carboxylic    acid ethyl ester (preparation 18),-   3-((1S,4R)-4-Chloro-cyclopent-2-enyl)-5-methyl-3H-imidazole-4-carboxylic    acid ethyl ester (preparation 19) or-   5-Methyl-3-[(1S,4S)-4-((R)-1-naphthalen-1-yl-ethylamino)-cyclopent-2-enyl]-3H-imidazole-4-carboxylic    acid ethyl ester (preparation 20).

Pharmaceutical Compositions

For use in therapy, compounds of the present invention are typically inthe form of a pharmaceutical composition. The invention thereforerelates to a pharmaceutical composition, both for veterinary (includingmammals such as horses, cattle, sheep, pigs, dogs and cats) and forhuman medical use, comprising a compound of formula I, optionallytogether with one or more other therapeutically active compound(s),together with a pharmaceutically acceptable excipient or vehicle. Theexcipient must be “acceptable” in the sense of being compatible with theother ingredients of the composition and not deleterious to therecipient thereof.

Conveniently, the active ingredient comprises from 0.05-99.9% by weightof the formulation, e.g. 0.5-90%, such as 5-85%, such as 15-45%,preferably 20-30%.

Pharmaceutical compositions of the invention may be in unit dosage formsuch as tablets, pills, capsules, powders, granules, elixirs, syrups,emulsions, ampoules, suppositories or parenteral solutions orsuspensions; for oral, parenteral, opthalmic, transdermal,intra-articular, topical, pulmonal, nasal, buccal or rectaladministration or in any other manner appropriate for the formulation ofcompounds used in nephrology and in accordance with accepted practicessuch as those disclosed in Remington: The Science and Practice ofPharmacy, 21^(St) ed., 2005, Lippincott Williams & Wilkins. In thecomposition of the invention, the active component may be present in anamount of from about 0.01 to about 99%, such as 0.1% to about 10% byweight of the composition.

For oral administration in the form of a tablet or capsule, a compoundof formula I may suitably be combined with an oral, non-toxic,pharmaceutically acceptable carrier such as ethanol, glycerol, water orthe like. Furthermore, suitable binders, lubricants, disintegratingagents, flavouring agents and colourants may be added to the mixture, asappropriate. Suitable binders include, e.g., lactose, glucose, starch,gelatin, acacia gum, tragacanth gum, sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes or the like.Lubricants include, e.g., sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride or the like.Disintegrating agents include, e.g., starch, methyl cellulose, agar,bentonite, xanthan gum or the like. Additional excipients for capsulesinclude macrogols or lipids.

For the preparation of solid compositions such as tablets, the activecompound of formula I is mixed with one or more excipients, such as theones described above, and other pharmaceutical diluents such as water tomake a solid preformulation composition containing a homogenous mixtureof a compound of formula I. The term “homogenous” is understood to meanthat the compound of formula I is dispersed evenly throughout thecomposition so that the composition may readily be subdivided intoequally effective unit dosage forms such as tablets or capsules. Thepreformulation composition may then be subdivided into unit dosage formscontaining from about 0.05 to about 1000 mg, in particular from about0.1 to about 500 mg, e.g. 10-200 mg, such as 30-180 mg, such as 20-50 mgof the active compound of the invention.

In the form of a dosage unit, the compound may be administered one ormore times a day at appropriate intervals, always depending, however, onthe condition of the patient, and in accordance with the prescriptionmade by the medical practitioner. Conveniently, a dosage unit of aformulation contain between 0.1 mg and 1000 mg, preferably between 1 mgand 100 mg, such as 5-50 mg of a compound of formula I.

A suitable dosage of the compound of the invention will depend, interalia, on the age and condition of the patient, the severity of thedisease to be treated and other factors well known to the practisingphysician. The compound may be administered either orally, parenterallyor topically according to different dosing schedules, e.g. daily or withweekly intervals. In general a single dose will be in the range from0.01 to 400 mg/kg body weight. The compound may be administered as abolus (i.e. the entire daily dosis is administered at once) or individed doses two or more times a day.

If the treatment involves administration of another therapeuticallyactive compound it is recommended to consult Goodman & Gilman's ThePharmacological Basis of Therapeutics, 9^(th) Ed., J. G. Hardman and L.E. Limbird (Eds.), McGraw-Hill 1995, for useful dosages of saidcompounds. The administration of a compound of the present inventionwith one or more other active compounds may be either concomitantly orsequentially.

Liquid formulations for either oral or parenteral administration of thecompound of the invention include, e.g., aqueous solutions, syrups,aqueous or oil suspensions and emulsion with edible oils such ascottonseed oil, sesame oil, coconut oil or peanut oil. Suitabledispersing or suspending agents for aqueous suspensions includesynthetic or natural gums such as tragacanth, alginate, acacia, dextran,sodium carboxymethylcellulose, gelatin, methylcellulose orpolyvinylpyrolidone.

For parenteral administration, e.g. intramuscular, intraperitoneal,subcutaneous or intravenous injection or infusion, the pharmaceuticalcomposition preferably comprises a compound of formula I dissolved orsolubilised in an appropriate, pharmaceutically acceptable solvent. Forparenteral administration, the composition of the invention may includea sterile aqueous or non-aqueous solvent, in particular water, isotonicsaline, isotonic glucose solution, buffer solution or other solventconventionally used for parenteral administration of therapeuticallyactive substances. The composition may be sterilised by, for instance,filtration through a bacteria-retaining filter, addition of asterilising agent to the composition, irradiation of the composition, orheating the composition. Alternatively, the compound of the inventionmay be provided as a sterile, solid preparation, e.g. a freeze-driedpowder, which is dissolved in sterile solvent immediately prior to use.

The composition intended for parenteral administration may additionallycomprise conventional additives such as stabilisers, buffers orpreservatives, e.g. antioxidants such as methylhydroxybenzoate or thelike.

Compositions for rectal administration may be in the form of asuppository incorporating the active ingredient and a carrier such ascocoa butter, or in the form of an enema.

Compositions suitable for intra-articular administration may be in theform of a sterile aqueous preparation of the active ingredient which maybe in microcrystalline form, for example, in the form of an aqueousmicrocrystalline suspension. Liposomal formulations or biodegradablepolymer systems may also be used to present the active ingredient forboth intra-articular and ophthalmic administration.

Compositions suitable for topical administration, including ophthalmictreatment, include liquid or semi-liquid preparations such as liniments,lotions, gels, applicants, oil-in-water or water-in-oil emulsions suchas creams, ointments or pastes; or solutions or suspensions such asdrops. For topical administration, the compound of formula I maytypically be present in an amount of from 0.01 to 20% by weight of thecomposition, such as 0.1% to about 10%, but may also be present in anamount of up to about 50% of the composition.

Compositions for ophthalmic treatment may preferably additionallycontain a cyclodextrin.

Compositions suitable for administration to the nasal or buccal cavityor for inhalation include powder, self-propelling and sprayformulations, such as aerosols and atomizers. Such compositions maycomprise a compound of formula I in an amount of 0.01-20%, e.g. 2%, byweight of the composition.

The composition may additionally comprise one or more other activecomponents conventionally used in the treatment of physiologicaldisorders or diseases associated with disturbances of CaSR activity,such as hyperparathyroidism.

A suitable dosage of the compound of the invention will depend, interalia, on the age and condition of the patient, the severity of thedisease to be treated and other factors well known to the practisingphysician. The compound may be administered orally, parenterally ortopically according to different dosing schedules, e.g. daily or withweekly intervals. In general a single dose will be in the range from0.01 to 400 mg/kg body weight. The compound may be administered as abolus (i.e. the entire daily dosis is administered at once) or individed doses two or more times a day.

Pharmacological Methods

The calcium sensing receptor (CaSR) and its use in identifying orscreening for calcimimetic compounds has been described in EP637237,EP1296142, EP1100826, EP1335978 and EP1594446.

In vitro and vivo methods for testing the compounds of the presentinvention are well established and may be found in the references listedabove, or e.g. in Journal of Biological Chemistry (2004), 279(8),7254-7263 or in U.S. Pat. No. 5,858,684 and references cited therein.

Biological Assay for Analysis of In Vitro Activity

The assay investigates a compound's functional ability to act as abiological positive modulator on the human CaSR. Activation of thereceptor expressed on CHO-K1 cells is detected through the G alpha qpathway, the activation of phospholipase C and the accumulation ofintracellular inositol phosphate (IP) as described earlier [SandrineFerry, Bruno Chatel, Robert H. Dodd, Christine Lair, Danielle Gully,Jean-Pierre Maffrand, and Martial Ruat, Effects of Divalent Cations andof a Calcimimetic on Adrenocorticotropic Hormone Release in PituitaryTumor Cells. Biochemical and biophysical research communications 238,866-873 (1997)]. The human CaSR is stably expressed on a CHO-K1 cellclone, stimulated with a basal level of calcium and challenged with thetested compound. The level of IP1 is determined using the IP-One htrfkit (Cisbio, France). CHO-K1 cells not transfected with the CaSR fail toelicit an IP1 response upon calcium and/or compound stimulation.

Cloning of the Human CaSR Gene

The ORF coding for the human CaSR (genebank: NM_(—)000388) was acquiredfrom Invitrogen Corp, USA and subsequently cloned into the mammalianexpression vector pCDA3.1.

Generation of Cell Line Expressing CaSR

CHO-K1 cells were transfected using Lipofectamine according tomanufacturer's protocol (400,000 cells/well were seeded in a 6-wellplate and transfected after 24 hours using 2 μg DNA and 5 μllipofectamine). After another 24 hours the cells were detached, seededand subjected to 1 mg/ml of G-418. Following 7 days growth single cloneswere picked, the CaSR expression evaluated using the 5C10 antibodyagainst CaSR, the clones with the highest expression were selected andtested for functional response. The preferred clone was continuouslycultured according to standard procedures described in ATCC (AmericanType Culture Collection) protocols for CHO-K1 with the addition of 500μg/ml G-418.

As described above, the compounds described in the present invention aremodulators of CaSR activity. The CaSR can be found in the parathyroidgland, the thyroid, bone cells, the stomach, the lung, the kidney,pituitary gland, the brain, the hypothalamus, the olfactory areas or thehippocampus. Compounds according to the present invention may preferablybe more selective, in their use, with respect to the receptors of theparathyroid compared with those of the thyroid gland.

The compounds according to the invention, and the pharmaceuticalcompositions comprising them, may be used as a medicinal product, inparticular for the treatment of physiological disorders or diseasesassociated with disturbances of CaSR activity. Even more particularly,these physiological disorders or diseases of the type including primaryor secondary hyperparathyroidism, osteoporosis, cardiovascular,gastrointestinal, endocrine or neurodegenerative diseases or certaincancers in which (Ca²⁺)_(e) ions are abnormally high. The secondaryhyperparathyroidism is more particularly observed in chronic renalfailure.

The following preparations and non-limiting examples are given in orderto enable a person skilled in the art to understand and to carry out theinvention.

The examples described in further detail in the following non-limitingexamples are not in any way intended to limit the scope of the inventionas claimed but are merely considered as being illustrative andrepresentative thereof.

Methods of Preparation

The compounds of general formula I can be prepared in a number of wayswell known to those skilled in the art of organic synthesis. Thecompounds of formula I can be synthesised using the methods outlinedbelow, together with methods known in the art of synthetic organicchemistry, or variations thereof as appreciated by those skilled in theart. Preferred methods include, but are not limited to, those describedbelow.

The compounds of formula I can be prepared by techniques and proceduresreadily available to one of ordinary skill in the art, for example byfollowing the procedures as set forth in the following schemes. Thereactions are performed in solvents appropriate to the reagents andmaterials employed and suitable for the transformations being effected.Also, in the synthetic methods described below, it is to be understoodthat all proposed reaction conditions, including choice of solvent,reaction atmosphere, reaction temperature, duration of experiment andwork-up procedures, are chosen to be conditions of standard for thatreaction, which should be readily recognised by one skilled in the art.It is understood by one skilled in the art of organic synthesis that thefunctionalities present on various portions of the starting molecules ina reaction must be compatible with the reagents and reactions proposed.Not all compounds of formula I falling into a given class may becompatible with some of the reaction conditions required in some of themethods described. Such restrictions to the substituents which arecompatible with the reaction conditions will be readily apparent to oneskilled in the art and alternative methods can be used.

The schemes described in this section are not intended to limit thescope of the invention in any way. All substituents, unless otherwiseindicated, are previously defined. The reagents and starting materialsare either available from commercial suppliers or prepared by methodsknown to one of ordinary skilled in the art following procedures setforth in references such as Fieser and Fieser's Reagents for OrganicSynthesis, Volumes 1-22 (John Wiley and Sons, 2004); Rodd's Chemistry ofCarbon Compounds, Volumes 1-5 and Supplements (Elsevier SciencePublishers, 2000); Organic Reactions, Volumes 1-64 (John Wiley and Sons,2004); March's Advanced Organic Chemistry (John Wiley and Sons, 5^(th)Edition) and Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1999). These schemes are merely illustrative of somemethods by which the compounds of this invention can be synthesised, andvarious modifications to these schemes can be made and will be suggestedto one skilled in the art having referred to this disclosure. Thestarting materials and the intermediates of the reactions may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallisation,chromatography and the like. Such materials may be characterised usingconventional means, including physical constants and spectral data.

Compounds of general formula I may be obtained by reductive aminationbetween a cyclic ketone of general formula II and an amine of generalformula III. The reaction between ketone II and amine III may be carriedout either by one-pot reductive amination or with isolation of the iminefollowed by reduction.

-   -   a. The formation of the intermediate iminium IV may be promoted        by addition of a protic or aprotic acid such as, but not limited        to acetic acid and Ti(Oi-Pr)₄ respectively. The reducing agent        may be but is not limited to Na(CN)BH₃, NaBH₄, Na(OAc)₃BH (for        other non-limiting conditions see Org. React. 2002, 59, 1-714        and references cited therein).    -   b. The formation of the imine is promoted either by Lewis acids        such as TiCl₄, ZnCl₂, AlCl₃ or by bases such as pyridine,        eventually in the presence of a drying agent such as TiCl₄ or        molecular sieve (see Comprehensive Organic Functionnal Group        Transformations 3, 403 (1995) Pergamon).    -   c. Reduction may be performed by hydrogenation in the presence        of a catalyst such as Pd/C, Pt/C or a chiral rhodium complex to        perform the reaction in a stereoselective manner or by hydride        transfer from a reducing agent such as BH₃, NaBH₄, NaBH₃CN,        LiAlH₄, L-selectride (see Larock R. C. Comprehensive Organic        Transformations 1989, VCH; Comprehensive Organic Functionnal        Group Transformations 2, 268-269 (2005) Pergamon and references        cited therein).

Compounds of general formula I may also be prepared through alkylationof the amine III.

-   -   d. When LG is a leaving group such as chloride, bromide, iodide,        tosylate or triflate, alkylation is performed in the presence of        a base such as NEt₃, DIPEA, NaH, NaOH, KOH, carbonates in an        appropriate solvent such as DMF, pyridine, DMSO, CH₃CN, acetone,        toluene. Alternatively reaction with an alcohol (LG=OH) may also        be considered. Such Mitsunobu-like reaction is performed in the        presence of a phosphine such as PBu₃, PPh₃ and the like, an        azodicarboxylate or an azodicarboxamide in an aprotic solvent,        typically THF. For this purpose the amine III is        protected/activated as a carbamate or a sulphonamide. The        resulting compound is deprotected using standard conditions        (Protective Groups in Organic Synthesis, T. W. Greene        and P. G. M. Wuts, John Wiley and Sons, 3^(rd) Edition 1999 and        reference sited therein) to afford I. The ketone II may be        prepared in various manners:

-   -   e. An alcohol Va may be oxidised to afford II. Oxidation may be        performed with many different reagents. A few of them are        H₂Cr₂O₇, Al₂O₃, MnO₂, periodinanes, DMSO in combination with        DCC, acetic anhydride, oxalyl chloride and the like.

Substituents G may be introduced through different pathways:

Cycloalkenones may be used as starting materials.

-   -   f. Coupling reaction with an aryl/heteroaryl halide or pseudo        halide such as triflate in the presence of a palladium source        such as Pd(OAc)₂, PdCl₂(PPh₃)₂, a base such as NEt₃, K₂CO₃,        NaHCO₃, eventually with a phosphine such PPh₃, P(o-Tol)₃,        1,3-bis(diphenylphosphino)propane (dppp), eventually in the        presence of a salt like NBu₄C1, AgNO₃ in a solvent such as DMF        or acetonitrile. Alternatively a decarboxylative Heck-type        coupling may be performed using an aryl/heteroaryl carboxylic        acid (Org. Lett. 2004, 6, 433).    -   g. Chemospecific reduction of the double bond may be performed        under numerous conditions. The hydrogen source may be H₂, water,        Hantzsch esters. Metal-based catalysts such as Pd/C, Pd(PPh₃)₄,        supported PdCl₂, Rh-, Co-, Cu-, Ir-based catalysts may be used.        Stereoselectivity may be achieved by addition of a chiral        auxiliary such as but not limited to enantiopure binaphtol        phosphate derivatives/valine, imidazolidinone iminiums,        bidentate phosphines.

Alternatively cycloalkenones may be subjected to 1,4-addition.

-   -   h. Reaction with an aryl/heteroaryl metal in which the metal may        be Li, Mg halide, trialkyltin, boronic acid eventually in the        presence of a metal complex such as PdCl₂, Pd(OAc)₂, Pd(PPh₃)₄,        (acac)Rh(CO)₂, Ni(acac)₂, (COD)Rh(1,4-dihydroquinone)BF₄ with a        ligand typically phosphine-based such as PBu₃, PPh₃,        1,3-bis(diphenylphosphino)propane (dppp), 1,3-hydroquinone or        1,4-hydroquinone in solvents such as DMF, THF, water, toluene,        dioxane, dimethoxyethane. In the presence of a chiral ligand as        a pure enantiomer such as BINAP, phosphoramidite, Me-DuPHOS and        the like the reaction may be performed stereoselectively.

1,4-Addition of heteroatom nucleophiles leads to compounds of generalformula I. The reaction may be catalysed by reagents such as but notlimited to NEt₃, ScCl₃, CAN, RuCl₃, PtCl₄ in solvents like CH₂Cl₂,CH₃CN, DMF, toluene.

Cycloalkan-1,3-diones may be used as starting materials.

-   -   i. Addition of an organometallic species such as GLi or GMgHal        (Hal=Cl, Br) affords a ketoalcohol II (R4=OH). Alternatively        addition of GBr under indium catalysis may lead to analogous        ketoalcohols II (R4=OH).

-   -   j. Substitution of a leaving group (LG) such as chloride,        bromide, iodide, tosylate or triflate by a nuceophile such as an        amine or an alcohol optionally in the presence of a base such as        NEt₃, NaH, NaOH, KOH, carbonates in an appropriate solvent such        as DMF, pyridine, DMSO, CH₃CN, acetone, toluene.

Cycloalkan-3-one carboxylates (II, G=CO-Q) are starting materials forvarious compounds of general formula I where the carboxylic group istransformed into amides or heterocycles. Some non-limiting examples aredepicted below.

-   -   k. The amide may be formed using an amine and a carboxylic acid        (II, G=COOH) in the presence of coupling agents such as        1,1′-carbonyldiimidazole (CDI), diphenylphosphinic chloride        (DPP-Cl), benzotriazol-yloxy-tripyrrolidinophosphonium        hexafluorophosphate (PyBOP),        benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium        hexafluorophosphate (BOP), pentafluorophenyl diphenylphosphinate        (fdpp),        N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium        hexafluorophosphate N-oxide (HATU),        bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP),        N,N′-dicyclohexylcarbodiimide (DCC), or        1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide; hydrochloride        (EDCI). The reaction may be performed in solvents such as        diethylether, dichloromethane, 1,2-dichloro-ethane,        tetrahydrofuran, 1-methyl-2-pyrrolidinone, dimethylsulfoxyde or        dimethylformamide. The reactions are generally carried out in        the presence of a base such as NEt₃, DIPEA, collidine or Bu₃N        and preferably in the presence of an activator such as HOBt (for        example where HOBt is used to improve reactions rates, see        Windridge, G. C.; Jorgensen, E. C. JACS 1971, 93, 6318) or HOAt.        The amide may also be formed through the reaction of the amine        III and a carboxylic acid chloride (II, G=COCl). The carboxylic        acid chloride may be prepared by reaction of the carboxylic acid        (II, G=COOH) with chlorinating agents such as thionyl chloride        or oxalyl chloride.    -   I. Carboxylic moiety may be converted into oxazoles by reaction        with 1,2-aminoalcohols, 1,2-aminoketones or 1,2-hydroxyketones        in the presence of a nitrogen source such as NH₄OAc typically        through formation of an amide (see condition k) followed by        cyclodehydration using reagents such as polyphosphoric acid,        p-toluenesulfonic acid, DBU/CBrCl₃ or DDQ in solvents such as        CCl₄, CH₂Cl₂, THF, dioxane or DMF.    -   m. Conversion to 1,2,4-oxadiazole may be achieved through        reaction with N-hydroxyamidines under amide-bond formation        condition (see k) followed by cyclodehydration in the presence        of dehydrating agents such as CDI. Alternatively reaction of        carboxylic esters (II, G=COOMe or COOEt) with N-hydroxyamidines        in presence of a base such as K₂CO₃ leads to 1,2,4-oxadiazole.        If not commercially available the N-hydroxyamidines may be        prepared by reacting N-hydroxylamine:hydrocloride with nitriles        in the presence of a base such as K₂CO₃, NaHCO₃, NEt₃, KOH or        MeONa.

If specific substitution patterns are needed on the carbocycle,synthesis of the carbocycles themselves may be considered. Many generalmethods are available among them are the Diels-Alder reaction, theRobinson annulation, the Birch reduction of aromatics the Pauson-Khandreaction, cyclopropanation of 1-methoxycycloalkene followed by ringexpansion, rearrangement of furans. For a comprehensive list seecomprehensive organic synthesis works cited earlier in this section.

A compound of general formula I may be obtained from another compound ofgeneral formula I by the mean of functional group interconversionwell-known to one skilled in the art of organic synthesis. This is ifany of R1 to R5 or a substituent on G or on A may be converted toanother functional group. These interconversions may be but are notlimited to reduction of a nitrile to an amine, hydrolysis of a nitrileto an amide or to an acid or hydrolysis of an ester.

Many of the general methods described above may be used in a differentorder whenever appropriate.

EXAMPLES General

For ¹H nuclear magnetic resonance (NMR) spectra (300 MHz) and ¹³C NMR(75.6 MHz) chemical shift values (δ) (in ppm) are quoted for dimethyl-d₆sulfoxide (DMSO-d₆) or CDCl₃ solutions relative to internaltetramethylsilane (δ=0) standard. The value of a multiplet, eitherdefined (doublet (d), triplet (t), quartet (q)) or not (m) at theapproximate mid point is given unless a range is quoted, (bs) indicatesa broad singlet. The ES mass spectra were obtained on a VG Quattro IItriple quadrapole mass spectrometer (Micromass, Manchester, UK)operating in either positive or negative electrospray mode with a conevoltage of 30V.

The microwave oven used was the model Initiator™ from Biotage.

The organic solvents used were anhydrous unless otherwise specified.Flash chromatography was performed on silica gel from Fluka Chemie GmbH,Switzerland. The phase separation cartridges used were Chromabond® fromMacherey-Nagel GmbH.

Chemicals unless otherwise noted were from commercial sources, e.g.Aldrich, Maybridge Chemical, Fluka or ABCR.

ABBREVIATIONS

-   acac acetylacetonate-   aq. aqueous-   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   Boc tert-butoxycarbonyl-   Bu₃N tributylamine-   CAN ceric ammonium nitrate-   CDI 1,1′-carbonyldiimidazole-   COD 1,5-cyclooctadiene-   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene-   DCC N,N′-dicyclohexylcarbodiimide-   DCE 1,2-dichloroethane-   DCM dichloromethane-   DDQ 2,3-dicyano-5,6-dichloro-parabenzoquinone-   DIAD diisopropyl azodicarboxylate-   DIPEA ethyl diisopropylamine-   DMAP dimethyl aminopyridine-   DMF N,N-Dimethylformamide-   DME 1,2-dimethoxyethane-   DMSO dimethyl sulfoxide-   EDAC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; hydrochloride-   eq. equivalent(s)-   ES Electro Spray-   EtOAc ethyl acetate-   h hour(s)-   HOAt 1-hydroxy-7-aza-benzotriazole-   HOBt hydroxybenzotriazole-   mCPBA meta-chloro perbenzoic acid-   Me-DuPhos 1,2-Bis[2,5-dimethylphospholano]benzene-   MTBE methyl tert-butyl ether-   nbd norbornadiene-   NBu₄Cl tetrabutylammoniumchloride-   NEt₃ triethylamine-   NMR nuclear magnetic resonance-   PBu₃ tributylphosphin-   PE petroleum ether (low boiling point)-   P(o-Tol)₃ tri(o-tolyl)-phosphin-   r.t. room temperature-   RT retention time-   sat. saturated-   THF tetrahydrofuran-   Ti(Oi-Pr)₄ titanium tetraisopropoxide-   TLC thin layer chromatography-   TMSCl chloro trimethylsilane

LC/MS Method A

Analytical HPLC/MS was performed on a Dionex APS-system with a P680Aanalytical pump and a Thermo MSQ Plus mass spectrometer (ionisationmode: ES+/ES−). Column: Waters XTerra C-18, 150 mm×4.6 mm, 5 μm; mobilephase: A=water (0.1% formic acid) and B=acetonitrile (0.1% formic acid);flow rate=1.0 mL/min; method (10 min): Linear gradient method going from10% B to 100% in 6.6 minutes and staying at 100% B for another 1.5minutes.

LC/MS Method B

Analytical HPLC/MS was performed on a Waters 2795 Alliance-system with aWaters 996 DAD analytical pump and a Waters ZQ Mass spectrometer(ionisation mode: ES+/ES−). Column: Waters Waters XBridge RP18 3.0×50mm, 5 μm; mobile phase: A=H₂O+0.05% HCOOH and B=CH₃CN+0.05% HCOOH; flowrate=1.0 mL/min; method (8 min): Linear gradient method going from 5% Bto 95% B in 6 minutes and staying at 95% B for another 1 minute.Retention time in UV chromatogram (RT) is given in minutes.

General Procedure A

To a solution of ketone (1 eq.) in 1,2-dichlorethane (0.38M) were addedthe amine (1 eq.), glacial AcOH (1 eq.) and NaBH(OAc)₃ (1.4 eq.). Themixture was stirred at r.t. overnight, filtered and concentrated invacuo. If necessary, purification was performed by continuous gradientflash chromatography.

Example 1 Cyclobutyl-((R)-1-naphthalen-1-yl-ethyl)-amine, hydrochloride(compound 1001)

General procedure A was followed using cyclobutanone (488 mg, 1.2 eq.)and (+)-(R)-1-naphthalen-1-yl-ethylamine (1 g). The solution was stirredfor 10 min before addition of 3 Å molecular sieves, glacial AcOH andNaBH(OAc)₃. After removal of the solvent the residue was taken in MeCN(20 mL) and treated with aq. 2N NaOH (10 mL), filtered and concentratedin vacuo. The residue was dissolved in EtOAc, washed with water,filtered and concentrated in vacuo. Chromatography (EtOAc-MeOH 100:0 to80:20) afforded the title compound. ¹³C NMR (75.5 MHz, DMSO) δ: 134.58,133.71, 130.61, 129.29, 129.25, 127.27, 126.48, 125.86, 125.06, 122.82,50.43, 50.16, 26.90, 20.63, 15.19.

General Procedure B

To a solution or a suspension of acid (1 eq.) in DMF (1M) under argonwas added CDI (1.2 eq.). The mixture was stirred at r.t. for 3 h beforeaddition of the amine (6 eq.). DIPEA (6 eq.) was added if the amine wasfurnished as the hydrochloride. Stirring was continued overnight at r.t.DMF was removed in vacuo. If necessary, purification was performed bycontinuous gradient flash chromatography.

Preparation 1: 3-((R)-1-naphthalen-1-yl-ethylamino)cyclobutanecarboxylic acid (compound 1000)

To a solution of 3-oxo-1-cyclobutane carboxylic acid (4.0 g) in1,2-dichlorethane (180 mL) were added(+)-(R)-1-naphthalen-1-yl-ethylamine (6.0 g), glacial AcOH (1 eq., 2.1mL) and NaBH(OAc)₃ (1.5 eq., 11.1 g). The mixture was stirred at r.t.for 48 h before removal of the solvent. The residue was treated with 1NNaOH (ca 100 mL) and pH was adjusted to 7 by addition of 4N HCl. Theoily precipitate was extracted with EtOAc. The solid formed uponextraction was filtered and washed with EtOAc to afford the titlecompound.

Example 2 3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid dimethylamide (compound 1002)

General procedure B was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 100 mg) and dimethylamine; hydrochloride (181 mg).Chromatography (CH₂Cl₂-MeOH/1% NEt₃ 100:0 to 70:30) afforded the titlecompound as an oil (mixture of 2 isomers. ¹³C NMR (75.5 MHz, DMSO) majorisomer δ: 174.53, 140.84, 133.98, 131.12, 129.02, 127.40, 125.87,125.69, 125.36, 123.06, 122.79, 51.12, 49.31, 36.71, 35.48, 33.38,32.84, 31.59, 23.35.

Example 3 3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid amide (compound 1003)

General procedure B was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 155 mg) and aq. NH₃ (2.5 mL). Chromatography(CH₂Cl₂-MeOH 90:10 to 70:30) afforded the title compound.

LC-MS (method B): RT=1.53, [M+H]⁺=269.3, [M−H]⁻=267.4.

Example 4(4-Methyl-piperazin-1-yl)-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutyl]-methanone;hydrochloride (compound 1004)

General procedure B was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 100 mg) and N-methylpiperazine (3 eq.). An extractivework-up (EtOAc and water) was performed before chromatography(CH₂Cl₂-MeOH 95:5 to 70:30). The resulting oil was treated with HCl. Theprecipitate was filtered to afford the title compound.

LC-MS (method B): RT=1.37, [M+H]⁺=352.3.

Example 5 3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid cyclopropylamide (compound 1005)

General procedure B was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 100 mg) and cyclopropylamine. Chromatography(CH₂Cl₂-MeOH/1% NEt₃ 100:0 to 70:30) afforded the title compound. LC-MS(method B): RT=2.2, [M+H]⁺=309.3.

Example 6 3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid isopropylamide (compound 1006)

General procedure B was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 100 mg) and isopropylamine. Chromatography(CH₂Cl₂-MeOH/1% NEt₃ 100:0 to 70:30) afforded the title compound. LC-MS(method B): RT=2.3, [M+H]⁺=311.3.

Example 7 3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid propylamide (compound 1007)

General procedure B was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 100 mg) and propylamine. Chromatography (CH₂Cl₂-MeOH/1%NEt₃ 100:0 to 70:30) afforded the title compound. LC-MS (method B):RT=2.3, [M+H]⁺=311.1.

Example 8 Morpholin-4-yl-[3-((R)-1-naphthalen-1-yl-ethylamino)cyclobutyl]-methanone (compound 1008)

General procedure B was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 100 mg) and morpholine. Chromatography (CH₂Cl₂-MeOH/1%NEt₃ 100:0 to 70:30) afforded the title compound as an oil. LC-MS(method B): RT=2.16, [M+H]⁺=339.3.

Example 9 3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid tert-butylamide (compound 1009)

General procedure B was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 100 mg) and tert-butylamine. Chromatography(CH₂Cl₂-MeOH/1% NEt₃ 100:0 to 70:30) afforded the title compound as anoil. LC-MS (method B): RT=2.6, [M+H]⁺=325.3.

Example 10 3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid ethylamide (compound 1010)

General procedure B was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 100 mg) and ethylamine. Chromatography (CH₂Cl₂-MeOH/1%NEt₃ 100:0 to 70:30) afforded the title compound as an oil. LC-MS(method B): RT=2.13, [M+H]⁺=297.2.

Example 11 3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid methoxy-methyl-amide; hydrochloride (compound 1011)

General procedure B was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 100 mg) and N,O-dimethylhydroxyl-amine; hydrochloride.Chromatography (CH₂Cl₂-MeOH/1% NEt₃ 100:0 to 70:30) afforded the titlecompound as an oil. LC-MS (method B): RT=2.17/2.31, [M+H]⁺=313.2.

General Procedure C

To a solution or a suspension of acid (1 eq.) in DMF (1M) under argonwas added CDI (1.2 eq.). The mixture was stirred at r.t. for ×h beforeaddition of the N-hydroxyamidine (1.2 eq.). Stirring was continued atr.t. for y h. CDI (1.2 eq.) was added and the mixture was heated to 115°C. for 1.5 h. The mixture was cooled to r.t., washed with water, NaHCO₃and brine, dried over MgSO₄, filtered and concentrated in vacuo. Ifnecessary, purification was performed by continuous gradient flashchromatography.

Example 12[3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclobutyl]-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1012)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 150 mg) and N′-hydroxy-2-methylpropaninnidamide (x=3 h,y=48 h). Chromatography (PE-EtOAc 100:0 to 40:60) afforded an oil whichwas treated with 4N HCl in dioxane. Precipitation occurred upon additionof Et₂O. The light-yellow precipitate was filtered and dried in vacuo toafford the title compound. ¹³C NMR (150.9 MHz, DMSO) δ: 180.68, 174.28,133.70, 133.25, 130.19, 129.05, 128.86, 126.90, 126.13, 125.43, 124.68,122.45, 50.23, 48.16, 39.97, 30.09, 25.92, 25.72, 20.09.

Example 13((R)-1-Naphthalen-1-yl-ethyl)-{3-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclobutyl}-amine;hydrochloride (compound 1013)

General procedure C was followed using 3-oxo-1-cyclobutane carboxylicacid (1.41 g, 12.4 mmol) and 3-trifluoromethyl-N-hydroxy-benzamidine(x=1 h, y=17 h). Chromatography (PE-EtOAc 80:20 to 70:30) afforded3-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclobutanone(compound 1112).

General procedure A was followed using3-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclobutanone(690 mg) and (+)-(R)-1-naphthalen-1-yl-ethylamine. The mixture wasworked up as follows. Et₂O was added to the reaction mixture. Theorganic phase was washed with aq. NaOH (1N), water and brine, dried overMgSO₄, filtered and concentrated in vacuo. Chromatography (PE-EtOAc80:20 to 60:40) afforded an oil which was treated with 4N HCl indioxane. Precipitation occurred upon addition of Et₂O and trituration.The colourless precipitate was filtered and dried in vacuo to afford thetitle compound. LC-MS (method B): RT=3.28, [M+H]⁺=438.2.

Example 14[3-(3-Methyl-[1,2,4]oxadiazol-5-yl)-cyclobutyl]-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1014)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 150 mg) and N′-hydroxy-ethanimidamide (x=2 h, y=48 h).Chromatography (PE-EtOAc 100:0 to 40:60) afforded an oil which wastreated with 4N HCl in dioxane. Precipitation occurred upon addition ofEt₂O and trituration. The light-yellow precipitate was filtered anddried in vacuo to afford the title compound. LC-MS (method B): RT=2.31,[M+H]⁺=308.2.

Example 15((R)-1-Naphthalen-1-yl-ethyl)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-cyclobutyl]-amine;hydrochloride (compound 1015)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 150 mg) and benzamidoxime (x=2 h, y=22 h).Chromatography (PE-EtOAc 100:0 to 50:50) afforded a light yellow oilwhich was treated with 4N HCl in dioxane. Precipitation occurred uponaddition of Et₂O. The precipitate was filtered and dried in vacuo toafford the title compound. LC-MS (method B): RT=3.04, [M+H]⁺=370.3.

Example 16((R)-1-Naphthalen-1-yl-ethyl)-{3-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclobutyl}-amine;hydrochloride (compound 1016)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 150 mg) and 4-trifluoromethylbenzamidoxime (x=2 h, y=22h). Chromatography (PE-EtOAc 100:0 to 50:50) afforded an oil which wastreated with 4N HCl in dioxane. Precipitation occurred upon addition ofEt₂O. The precipitate was filtered and dried in vacuo to afford thetitle compound. LC-MS (method B): RT=3.52, [M+H]⁺=438.2.

Example 17{3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclobutyl}-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1017)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(preparation 1, 150 mg) and 4-methoxybenzamidoxime (x=1 h, y=22 h).Chromatography (PE-EtOAc 100:0 to 40:60) afforded an oil which wastreated with 4N HCl in dioxane. Precipitation occurred upon addition ofEt₂O. The precipitate was filtered and dried in vacuo to afford thetitle compound. LC-MS (method B): RT=3.14, [M+H]⁺=400.3.

Preparation 2: 3-Oxocyclobutane carbonyl chloride

Oxalylchloride (1.5 eq.) was added dropwise to a solution of3-oxocyclobutane carboxylic acid (56 mmol) in CH₂Cl₂ and DMF (1 drop)under argon. The solution was stirred at r.t. for 30 min before beingconcentrated in vacuo to afford the crude 3-oxocyclobutane carbonylchloride used without further purification.

General Procedure D

To a solution of the acid chloride (preparation 2, 1.2 mmol) in1,2-dichloroethane (0.5 mL) was added the amine (1.2 mmol) as aCH₂Cl₂-solution (1 mL) and NEt₃ (1.5 eq.). The mixture was shaken atr.t. overnight. 0.5M aq. HCl (0.5 mL) was added and the mixture wasshaken at r.t. for 2 h. Filtration through a phase separation cartridgeafforded the organic phase which was concentrated in vacuo to give acrude amide used without further purification.

To a solution of the amide (1.2 mmol) in 1,2-dichloroethane (1 mL) wereadded (+)-(R)-1-naphthalen-1-yl-ethylamine (1 eq.) and glacial AcOH (2eq.). The mixture was shaken for 2 h before addition of NaHB(OAc)₃ (1.5eq.). Shaking was continued at r.t. overnight before filtration andconcentration in vacuo. The residue was dissolved in DMSO (1 mL). 0.1 mLof this solution was purified by preparative HPLC-MS, re-analysed byHPLC-MS method A.

Example 18 3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid 4-chloro-benzylamide (compound 1018)

General procedure D was followed using 4-chlorobenzylamine to afford thetitle compound as a mixture of 2 isomers in almost equal amount. LC/MS(METHOD A): (m/z) 393.1 (MH+); RT (UV)=5.11 min. ¹H NMR (500 MHz, DMSO)δ_(H) 8.26 (t, 1H), 8.14-8.20 (m, 1H), 7.91 (d, 1H), 7.78 (d, 1H), 7.67(t, 1H), 7.42-7.56 (m, 3H), 7.33 (dd, 2H), 7.19 (dd, 2H), 4.49-4.64 (m,1H), 4.18 (dd, 1H), 2.80-3.03 (m, 2H), 1.79-2.24 (m, 4H), 1.36 (d, 3H)(one CH hidden by water-signal). LC-MS (method B): RT=5.11,[M+H]⁺=393.1.

Example 19{[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-aceticacid methyl ester (compound 1019)

General procedure D was followed using 2-aminoacetic acid methyl ester;

hydrochloride. LC-MS (method B): RT=4.32, [M+H]⁺=341.0.

Example 20 3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid (2-methoxy-ethyl)-amide (compound 1020)

General procedure D was followed using 2-methoxyethylamine. LC-MS(method B): RT=4.12, [M+H]⁺=327.1.

Example 214-{[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-benzoicacid ethyl ester (compound 1021)

General procedure D was followed using 4-aminobenzoic acid ethyl ester.LC-MS (method B): RT=5.12, [M+H]⁺=417.2.

Example 22 (2,6-Dimethyl-morpholin-4-yl)-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutyl]-methanone (compound 1022)

General procedure D was followed using 2,6-dimethylmorpholine. LC-MS(method B): RT=4.56, [M+H]⁺=367.1.

Example 23 3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid (3-morpholin-4-yl-propyl)-amide (compound 1023)

General procedure D was followed using 1-morpholino-3-aminopropane.LC-MS (method B): RT=3.54, [M+H]⁺=396.2.

Example 241-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-piperidine-4-carboxylicacid ethyl ester (compound 1024)

General procedure D was followed using piperidine-4-carboxylic acidethyl ester. LC-MS (method B): RT=4.81, [M+H]⁺=409.2.

Example 25 3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid (2-hydroxy-2-phenyl-ethyl)-amide (compound 1025)

General procedure D was followed using 2-hydroxy-2-phenyl-ethylamine.LC-MS (method B): RT=4.59, [M+H]⁺=389.1.

Example 263-{[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-propionicacid ethyl ester (compound 1026)

General procedure D was followed using 3-aminopropionic acid ethylester; hydrochloride. LC-MS (method B): RT=4.57, [M+H]⁺=369.1.

Example 27[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutyl]-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone(compound 1027)

General procedure D was followed using4-(3-trifluoromethyl-phenyl)-piperazine. LC-MS (method B): RT=5.56,[M+H]⁺=482.1.

Example 28{[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-phenyl-aceticacid methyl ester (compound 1028)

General procedure D was followed using (R)-(−)-2-phenylglycin methylester; hydrochloride. LC-MS (method B): RT=4.86, [M+H]⁺=417.1.

Example 29 3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid (2-hydroxy-indan-1-yl)-amide (compound 1029)

General procedure D was followed using (1S,2R)-(−)cis-1-amino-2-indanol. LC-MS (method B): RT=4.67, [M+H]⁺=401.2.

Example 30[4-(2-Methoxy-ethyl)-piperazin-1-yl]-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutyl]-methanone(compound 1030)

General procedure D was followed using 4-(2-methoxy-ethyl)-piperazine.LC-MS (method B): RT=3.52, [M+H]⁺=396.2.

Example 31 3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid 2,3,6-trifluoro-benzylamide (compound 1031)

General procedure D was followed using 2,3,6-trifluoro benzylamine.LC-MS (method B): RT=4.99, [M+H]⁺=413.1.

Example 32 3-({[3-((R)-1-Naphthalen-1-yl-ethylamino)cyclobutanecarbonyl]-amino}-methyl)-benzoic acid methyl ester (compound1032)

General procedure D was followed using 3-aminomethyl benzoic acid methylester: hydrochloride. LC-MS (method B): RT=4.81, [M+H]⁺=417.1.

Example 334-({[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-methyl)-benzoicacid methyl ester (compound 1033)

General procedure D was followed using 4-aminomethyl benzoic acid methylester. LC-MS (method B): RT=4.79, [M+H]⁺=417.1.

Example 34{[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-phenyl-aceticacid (compound 1034)

To a solution of{[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-phenyl-aceticacid methyl ester (ex. 28, 1.2 mmol) in MeOH (1 mL) were added water(0.3 mL) and LiOH (10 eq.). The mixture was shaken at r.t. overnight.Aq. HCl (4N) was added until pH=5. Solvent was decanted and theremaining oil was washed with EtOAc, dried in vacuo and purified bypreparative HPLC-MS. LC-MS (method B): RT=2.47, [M+H]⁺=403.3,[M−H]⁻=401.4

Example 35 ((R)-1-Naphthalen-1-yl-ethyl)-(3-phenyl-cyclobutyl)-amine(compound 1035 and compound 1036)

General procedure A was followed using 3-phenylcyclobutanone (1.0 g) and(+)-(R)-1-naphthalen-1-yl-ethylamine. Chromatography (PE-EtOAc-MeOH100:0:0 to 0:100:0 to 0:80:20) afforded the title compound (compound1035), and the title compound (compound 1036). LC-MS (method B):compound 1035: RT=2.22, [M+H]⁺=302.2; compound 1036: RT=2.28,[M+H]⁺=302.2.

Preparation 3:3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid(compound 1111)

To a solution of 3-oxo-1-cyclopentane carboxylic acid (5.3 g) in1,2-dichlorethane (100 mL) were added(+)-(R)-1-naphthalen-1-yl-ethylamine (7.1 g), glacial AcOH (1 eq., 2.4mL) and NaBH(OAc)₃ (1.5 eq., 13.1 g). The mixture was stirred at r.t.for 4 h before removal of the solvent. The residue was treated with sat.aq. NaNCO₃, pH was adjusted to 7 by addition of glacial AcOH. Extraction(5 times) was performed with EtOAc. The combined extracts were driedover MgSO₄, filtered and concentrated in vacuo to afford an oil whichupon trituration in EtOAc precipitated. Filtration afforded the titlecompound

The pH of the aq. phase was adjusted to 6 with 4N HCl, upon standingprecipitation occurred. Filtrations afforded more of the title compound.

Example 36{3-[3-(4-Fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopentyl}-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1037)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid(preparation 3, 205 mg) and N′-hydroxy-(4-fluorophenyl)imidamide (x=24h, y=5 h). Chromatography (PE-EtOAc 100:0 to 40:60) afforded an oilwhich was treated with 4N HCl in dioxane. Precipitation occurred uponaddition of Et₂O. The light-yellow precipitate was filtered and dried invacuo to afford the title compound. ¹N NMR (300 MHz, DMSO) δ_(H): 10.22(s, 1H), 9.60 (s, 1H), 8.34 (d, 1H), 7.91-8.14 (m, 6H), 7.54-7.73 (m,3H), 7.30-7.47 (m, 2H), 5.36 (q, 1H), 3.74-3.93 (m, 1H), 3.50-3.69 (m,1H), 2.21-2.44 (m, 3H), 1.95-2.18 (m, 2H), 1.78-1.90 (m, 1H), 1.75 (d,3H).

Example 37((R)-1-Naphthalen-1-yl-ethyl)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-cyclopentyl]-amine;hydrochloride (compound 1038)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid(preparation 3, 205 mg) and benzamidoxime (x=24 h, y=5 h).Chromatography (PE-EtOAc 100:0 to 40:60) afforded an oil which wastreated with 4N HCl in dioxane. Precipitation occurred upon addition ofEt₂O. The light-yellow precipitate was filtered and dried in vacuo toafford the title compound. LC-MS (method B): RT=2.94, [M+H]⁺=384.2.

Example 38[3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclopentyl]-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1039)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid(preparation 3, 194 mg) and N′-hydroxy-2-methylpropanimidamide (x=24 h,y=4 h). Chromatography (PE-EtOAc 100:0 to 40:60) afforded an oil whichwas treated with 4N HCl in dioxane. Precipitation occurred upon additionof Et₂O. The light-yellow precipitate was filtered and dried in vacuo toafford the title compound. ¹H NMR (300 MHz, DMSO) as free amine δ_(H)8.22-8.35 (m, 1H), 7.87-7.97 (m, 1H), 7.68-7.82 (dd, 2H), 7.44-7.59 (m,3H), 4.64 (q, 1H), 3.45-3.66 (m, 1H), 3.04-3.19 (m, 1H), 2.88-3.03 (m,1H), 2.34 (bs, 1H), 2.00-2.25 (m, 2H), 1.41-1.95 (m, 5H), 1.37 (d, 3H),1.19 (d, 6H).

Example 39((R)-1-Naphthalen-1-yl-ethyl)-{3-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopentyl}-amine;hydrochloride (compound 1040)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid(preparation 3, 195 mg) andN′-hydroxy-(4-trifluoromethylphenyl)imidamide (x=24 h, y=4 h).Chromatography (PE-EtOAc 100:0 to 40:60) afforded an oil which wastreated with 4N HCl in dioxane. Precipitation occurred upon addition ofEt₂O. The colourless precipitate was filtered and dried in vacuo toafford the title compound. LC-MS (method B): RT=3.21, [M+H]⁺=452.1.

Example 40[3-(3-Methyl-[1,2,4]oxadiazol-5-yl)-cyclopentyl]-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1041)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid(preparation 3, 190 mg) and N′-hydroxy-acetamidine (x=1 h, y=20 h).Chromatography (PE-EtOAc 100:0 to 40:60) afforded an oil which wastreated with 4N HCl in dioxane. Precipitation occurred upon addition ofEt₂O. The precipitate was filtered and dried in vacuo to afford thetitle compound. ¹H NMR (300 MHz, DMSO) δ_(H) 10.26 (s, 1H), 9.45 (s,1H), 8.31 (d, 1H), 7.90-8.12 (m, 3H), 7.50-7.70 (m, 3H), 5.35 (q, 1H),3.63-3.81 (m, 1H), 3.44-3.62 (m, 1H), 2.00-2.33 (m, 4H), 2.24 (s, 3H),1.90 (s, 1H), 1.73 (d, 3H), 1.65-1.79 (m, 1H).

Example 41{3-[3-(5-Methyl-thiazol-2-ylmethyl)-[1,2,4]oxadiazol-5-yl]-cyclopentyl}-((R)-1-naphthalen-1-yl-ethyl)-amine (compound 1042)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid(preparation 3, 190 mg) andN-hydroxy-2-(5-methyl-thiazol-2-yl)-acetamidine (x=4 h, y=20 h).Chromatography (PE-EtOAc 100:0 to 30:70 then CH₂Cl₂-MeOH 98:2 to 80:20)afforded the title compound. LC-MS (method B): RT=2.68, [M+H]⁺=419.

Example 42((R)-1-naphthalen-1-yl-ethyl)-[3-(3-propyl-[1,2,4]oxadiazol-5-yl)-cyclopentyl]-amine;hydrochloride (compound 1043a and 1043b)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid(preparation 3, 190 mg) and N′-hydroxy-butyramidine (x=4 h, y=20 h).Chromatography (PE-EtOAc 100:0 to 30:70) afforded an oil which wastreated with 4N HCl in dioxane. Precipitation occurred upon addition ofEt₂O. The precipitate was filtered and dried in vacuo to afford thetitle compound as 2 isomers. ¹³C NMR (75.5 MHz, DMSO) major isomer δ:183.03, 170.02, 142.44, 133.85, 131.34, 129.01, 126.95, 126.09, 125.98,125.62, 123.35, 56.50, 51.48, 37.54, 34.81, 33.20, 29.43, 27.43, 24.64,20.10, 13.74.

Example 431-{5-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-[1,2,4]oxadiazol-3-ylmethyl}-1H-pyridin-2-one;hydrochloride (compound 1044)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid(preparation 3, 190 mg) andN-hydroxy-2-(2-oxo-2H-pyridin-1-yl)-acetamidine (x=5 h, y=19 h).Chromatography (PE-EtOAc 60:40 to 0:100 then CHCl₃-MeOH 100:0 to 90:10)afforded an oil which was treated with 4N HCl in dioxane. Precipitationoccurred upon addition of Et₂O. The precipitate was filtered and driedin vacuo to afford the title compound.

LC-MS (method B): RT=2.23, [M+H]⁺=415.3.

Example 44{3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopentyl}-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1045)

General procedure C was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid(preparation 3, 190 mg) and N′-hydroxy-(4-methoxyphenyl)imidamide (x=4h, y=20 h). Chromatography (PE-EtOAc 100:0 to 30:70 then CH₂Cl₂-MeOH90:10 to 70:30) afforded an oil which was treated with 4N HCl indioxane. Precipitation occurred upon addition of Et₂O. The precipitatewas filtered and dried in vacuo to afford the title compound.

LC-MS (method B): RT=3.11, [M+H]⁺=414.1.

Example 45 3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentanecarboxylicacid amide

(compound 1046)

General procedure B was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid(preparation 3, 155 mg) and aq. NH₃ (2.5 mL). Chromatography(CH₂Cl₂-MeOH 90:10 to 70:30) afforded the title compound.

LC-MS (method B): RT=1.93, [M+H]⁺=283.2.

Example 46 4-Methyl-N-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarbonyl]-benzenesulfonamide (compound 1047a, compound 1047b, compound1047c and compound 1047d)

To a stirred mixture of 3-oxocyclopentanecarboxylic acid (1.2 g) andNEt₃ (1.56 mL) in THF (50 mL) under argon was added dropwise4-methyl-benzenesulfonyl isocyanate (1.71 mL). Stirring was continued atr.t. for 1 h before addition of N,N′-dimethyl-1,3-propane diamine.Stirring was continued at r.t. for 10 min. The mixture was diluted withEtOAc, washed with aq. HCl (1M) and brine, dried over Na₂SO₄, filteredand concentrated in vacuo to afford4-methyl-N-(3-oxo-cyclopentanecarbonyl)-benzenesulfonamide (compound1113) used without further purification.

General procedure A was followed using4-methyl-N-(3-oxo-cyclopentanecarbonyl)-benzenesulfonamide (1.9 g) and(+)-(R)-1-naphthalen-1-yl-ethylamine with a reaction time of 4 h. Themixture was diluted with CH₂Cl₂, washed with sat. aq. NaHCO₃, and brine,dried over Na₂SO₄, filtered and concentrated in vacuo to afford a yellowfoam. The foam was treated with hot EtOH. The precipitate formed uponcooling was filtered, washed with EtOH to afford the title compound as awhite powder. LC-MS (method B): RT (4 isomers)=3.02, 3.10, 3.37, 4.10,[M+H]⁺=437.4, [M−H]⁻=435.4.

Example 474-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzonitrile(compounds 1048/1049/1050)

General procedure A was followed using 3-(4-cyanophenyl)cyclohexanone (5g) and (+)-(R)-1-naphthalen-1-yl-ethylamine (3.7 mL). Chromatography(Heptane-EtOAc 100:0 to 0:100) afforded the title compound as a solid(fraction A), the title compound as an oil (fraction B) and the titlecompound as an oil (fraction C). Fractions A and B contained singlediastereomers: compound 1048 and compound 1049 respectively. Fraction Ccontained a mixture of 2 diastereomers: compound 1050. Compound 1048 ¹³CNMR (75.5 MHz, DMSO) δ: 153.24, 142.40, 133.48, 132.00, 130.84, 128.62,127.76, 126.46, 125.64, 125.55, 125.17, 123.07, 122.97, 118.92, 108.37,51.09, 50.03, 38.25, 37.30, 32.69, 28.86, 24.59, 20.15. Compound 1049¹³C NMR (75.5 MHz, DMSO) δ: 153.25, 142.12, 133.43, 132.09, 130.87,128.60, 127.96, 126.46, 125.67, 125.54, 125.17, 122.97, 122.85, 118.97,108.42, 50.17, 49.28, 37.07, 36.17, 32.84, 30.61, 24.38, 20.39. Compound1050 (2 isomers ca. 2:1) ¹³C NMR (75 MHz, DMSO) δ: 152.65, 152.58,142.13, 141.99, 133.46, 133.44, 132.20, 130.79, 130.76, 128.61, 128.59,127.80, 126.50, 125.71, 125.67, 125.60, 125.19, 122.94, 122.87, 122.83,122.72, 118.92, 108.65, 108.63, 53.79, 53.62, 49.30, 49.16, 42.67,42.41, 40.71, 39.96, 33.25, 33.07, 32.15, 24.74, 24.49, 24.33.

General Procedure E

To a solution of nitrile (1 eq.) in EtOH (0.12 M) were added K₂CO₃ (12eq.) and hydroxylamine; hydrochloride (7 eq.). The mixture was stirredat reflux overnight. After filtration the filter-cake was extracted withhot EtOH. The combined extracts were concentrated in vacuo. Ifnecessary, purification was performed by continuous gradient flashchromatography.

Example 48N-Hydroxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamidine(compound 1051)

General procedure E was followed using4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzonitrile (ex.47, fraction A, 500 mg) and hydroxylamine; hydrochloride. Chromatography(PE-EtOAc-MeOH 100:0:0 to 0:100:0 to 0:80:20) afforded the titlecompound as a colourless solid. ¹³C NMR (75.5 MHz, DMSO) δ: 150.76,148.10, 142.43, 133.47, 130.84, 130.69, 128.60, 126.42, 126.25, 125.61,125.55, 125.16, 123.09, 122.96, 51.01, 50.14, 38.72, 36.78, 33.14,29.04, 24.59, 20.30.

Example 49N-Hydroxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamidine(compound 1052)

General procedure E was followed using4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzonitrile (ex.47, fraction B, 500 mg) and hydroxylamine; hydrochloride. Chromatography(PE-EtOAc-MeOH 100:0:0 to 0:100:0 to 0:50:50) afforded the titlecompound as a yellow oil. ¹³C NMR (75.5 MHz, DMSO) δ: 167.78, 150.81,148.11, 142.13, 133.43, 130.86, 130.81, 128.60, 127.44, 126.44, 125.66,125.54, 125.29, 125.15, 122.99, 122.83, 50.19, 49.38, 36.58, 33.38,30.78, 24.42, 20.55.

Example 50N-Hydroxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamidine(compound 1053a and compound 1053b)

General procedure E was followed using4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzonitrile (ex.47, fraction C, 100 mg) and hydroxylamine; hydrochloride. Chromatography(PE-EtOAc-MeOH 100:0:0 to 0:100:0 to 0:90:10) afforded the titlecompound. ¹³C NMR (75.5 MHz, DMSO) δ: 168.18, 151.20, 151.20, 148.10,148.04, 142.76, 142.66, 133.88, 131.42, 131.23, 129.04, 127.94, 126.87,126.71, 126.04, 125.77, 125.60, 123.32, 123.24, 123.17, 54.37, 54.23,49.65, 42.88, 42.61, 41.83, 40.98, 34.04, 32.83, 25.33, 25.09, 24.88 (2isomers in almost equal amount).

Example 51{3-[4-(Imino-pyrrolidin-1-yl-methyl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1054)

To a solution of4-[3-(R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzonitrile (ex. 47,fraction A, 150 mg) in MeOH (1.5 mL) under argon were addedN-acetylcysteine (7 eq.) and pyrrolidine (7.4 eq.). The mixture wasstirred at 70° C. for 4 days. MeoH was removed in vacuo. The residue wastaken in water and extracted with CH₂Cl₂ (4 times). The combinedextracts were concentrated in vacuo and purified by continuous gradientflash chromatography (CH₂Cl₂-MeOH 100:0 to 50:50) to afford the titlecorn pound.

LC-MS (method B): RT=2.01, [M+H]⁺=426.3.

Example 52 4-[3-((R)-1-naphthalen-1-yl-ethylamino)cyclohexyl]-benzamidine (compound 1055)

To a solution ofN-hydroxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamidine(ex 48, 200 mg) in EtOAc (10 mL) was added SnCl₂.2H₂O (3 eq.). Themixture was stirred at reflux overnight. After cooling to r.t. themixture was diluted with EtOAc and washed with aq. sat. NaHCO₃. The org.phase was chromatographed (PE-EtOAc 100:0 to 0:100 to EtOAc-MeOH 90:10)to afford the title compound. LC-MS (method B): RT=1.92, [M+H]⁺=372.3.

General Procedure F

To a solution of benzonitrile in MeOH (0.09 M, y mL) was added 28% aqNaOH (y/2 mL). The mixture was heated to reflux overnight. MeOH wasremoved under reduced pressure. The residue was taken in water and 4Naq. HCl was added until pH=5. The precipitate was collected, washed withwater and dried in vacuo.

Example 53 4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid (compound 1056)

General procedure F was followed using4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzonitrile (ex.47, fraction A, 3.5 g) afforded the corresponding acid. ¹³C NMR (75.5MHz, DMSO) δ: 167.33, 152.18, 142.11, 133.49, 130.83, 129.16, 128.72,128.62, 126.66, 126.54, 125.68, 125.57, 125.20, 123.19, 122.96, 51.12,50.24, 38.38, 37.04, 32.81, 28.90, 24.45, 20.22.

Example 54 4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid (compound 1057)

General procedure F was followed using4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzonitrile (ex.47, fraction B, 0.8 g) afforded the corresponding acid. ¹³C NMR (75.5MHz, DMSO) δ: 167.27, 151.71, 140.47, 133.43, 130.73, 129.26, 128.68,128.54, 126.93, 126.85, 125.96, 125.55, 125.36, 123.33, 122.71, 50.10,49.71, 36.63, 35.45, 32.55, 30.15, 23.72, 20.29.

Example 55 4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid (compound 1058)

General procedure F was followed using4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzonitrile (ex.47, fraction C, 1.0 g) afforded the corresponding acids. ¹³C NMR (75MHz, DMSO) δ: 167.37, 150.91, 150.88, 133.37, 130.44, 130.38, 129.39,129.36, 129.34, 128.73, 128.70, 127.42, 127.38, 126.63, 126.58, 126.24,126.14, 125.55, 125.51, 123.58, 123.48, 122.65, 122.57, 53.96, 53.79,49.04, 48.95, 42.04, 41.89, 38.71, 38.19, 32.87, 31.30, 30.20, 24.32,24.11, 22.72.

Example 55a 4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid (compound 1058a)

¹H NMR (300 MHz, DMSO) δ 8.38-8.21 (m, 1H), 7.95-7.87 (m, 1H), 7.82 (d,2H), 7.75 (dd, 2H), 7.57-7.39 (m, 3H), 7.30 (d, 2H), 4.72 (dd, 1H),3.17-3.06 (m, 1H), 2.82 (m, 1H), 1.91-1.68 (m, 3H), 1.66-1.27 (m, 8H).

Example 56 3-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid ethyl ester (compound 1059)

General procedure A was followed using 3-(3-oxo-cyclohexyl)-benzoic acidethyl ester (10 g) and (+)-(R)-1-naphthalen-1-yl-ethylamine (6 mL).Chromatography (Heptane-EtOAc 100:0 to 0:100) afforded the titlecompound as a mixture of isomers. LC-MS (method B): RT=2.81,[M+H]⁺=402.2.

Example 57N-(2-Hydroxy-ethyl)-3-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1060)

To a solution of3-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid ethylester (ex. 56, 2.15 g) in anhydrous MeCN (25 mL) under argon were addedethanolamine (15 eq.) and K₂CO₃. The mixture was stirred at reflux for 2days. MeCN was removed in vacuo. The residue was taken in EtOAc, washedwith water, dried over MgSO₄, filtered and concentrated in vacuo.Chromatography (PE-EtOAc-MeOH 10:90:0 to 0:100:0 to 0:80:20) affordedthe title compound. LC-MS (method B): RT=2.13, [M+H]⁺=417.2,[M−H]⁻=415.4.

Example 58 3-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid (compounds 1061/1062)

To a solution of3-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid ethylester (10.4 g) in MeOH (200 mL) was added 2N aq. NaOH (100 mL). Thesolution was stirred at r.t. overnight and concentrated in vacuo. Theresidue was taken in water (150 mL) and 4N aq. HCl (ca 50 mL) was addeddropwise until pH=7 and the precipitate persisted. The acid was filteredwashed with water and dried in vacuo to afford the title compound as amixture of isomers. 100 mg were purified by preparative chiral HPLC toafford the title compound (fraction A, compound 1061) and the titlecompound (fraction B, compound 1062), each as single isomer. Preparativechiral HPLC was performed on a Chiralpak AD-H column 250×10 mm, 5 μm at25° C., UV detection at 280 nm. Isocratic separation withn-heptan:2-propanol:NEt₃:CH₃COOH (85:15:0.1:0.1); flow rate=3.0 mL/min.

Compound 1061: RT=13.4 min; ¹³C NMR (75.5 MHz, DMSO) δ: 168.11, 147.83,141.93, 133.86, 131.89, 131.45, 131.24, 129.06, 128.72, 128.00, 127.11,127.08, 126.20, 125.97, 125.66, 123.55, 123.22, 50.71, 50.07, 37.01,36.83, 33.62, 30.81, 24.56, 20.89. Compound 1062: RT=15.3 min; ¹³C NMR(75.5 MHz, DMSO) δ: 168.58, 147.67, 142.50, 133.89, 133.22, 131.30,130.75, 129.05, 128.39, 127.86, 127.01, 126.94, 126.11, 125.99, 125.60,123.47, 123.31, 51.04, 50.29, 39.23, 37.31, 33.60, 29.15, 24.80, 20.68.

Example 59 ((R)-1-Naphthalen-1-yl-ethyl)-(3 (S)-phenyl-cyclohexyl)-amine(compound 1063)

General procedure A was followed using (S)-3-phenylcyclohexanone (100mg) and (R)-(+)-1-naphthalen-1-yl-ethylamine. Chromatography(Heptane-EtOAc 85:15 to 0:100) afforded the title compound. LC-MS(method B): RT=2.42, [M+H]⁺=330.3.

Example 60 ((R)-1-Naphthalen-1-yl-ethyl)-(3 (R)-phenyl-cyclohexyl)-amine(compound 1064)

General procedure A was followed using (R)-3-phenylcyclohexanone (100mg) and (R)-(+)-1-naphthalen-1-yl-ethylamine. Chromatography(Heptane-EtOAc 90:10 to 0:100) afforded the title compound.

LC-MS (method B): RT=2.31, [M+H]⁺=330.3.

General Procedure G

To a mixture of an amine (1 eq.), a cycloalk-2-en-1-one (1.2 eq.) andPEG2000 (4 g for 10 mmol amine) at 60° C. was added RuCl₃ (3%). Themixture was stirred at 60° C. overnight. After cooling to r.t. Et₂O (20mL for 10 mmol) was added. The mixture was kept in the refrigerator for30 min before filtration of the precipitate. The solid was extractedwith Et₂O (3 times). The combined extracts were washed with water, driedover Na₂SO₄, filtered and concentrated in vacuo. If necessary,purification was performed by continuous gradient flash chromatography.

Example 61N—((R)-1-Naphthalen-1-yl-ethyl)-N′-phenyl-cyclohexane-1,3-diamine(compound 1065)

General procedure G was followed using aniline (0.91 mL) andcyclohex-2-en-1-one. Chromatography (CH₂Cl₂-MeOH 100:0 to 85:15)afforded 3-phenylamino-cyclohexa none.

Procedure A was followed using 3-phenylamino-cyclohexanone (41 mg) and(+)-(R)-1-naphthalen-1-yl-ethylamine. Chromatography (PE-EtOAc-MeOH100:0:0 to 0:100:0 to 0:90:10) afforded the title compound as a mixtureof 2 isomers in the ratio 1:3. ¹³C NMR (75.5 MHz, DMSO) δ: 147.94,142.31, 133.44, 130.77, 128.76, 128.65, 128.58, 126.37, 125.62, 125.59,125.52, 125.12, 122.93, 122.83, 115.01, 114.88, 112.20, 50.22, 49.80,49.59, 49.38, 46.15, 46.01, 37.77, 36.15, 31.78, 31.71, 29.97, 24.51,24.34, 19.60, 19.26.

Example 62N—((R)-1-Naphthalen-1-yl-ethyl)-N′-(3-trifluoromethyl-phenyl)-cyclohexane-1,3-diamine(compound 1066)

General procedure G was followed using 3-trifluoromethylaniline (1.61 g)and cyclohex-2-en-1-one. Chromatography (PE-EtOAc 100:0 to 0:100)afforded 3-(3-trifluoromethylphenyl)amino-cyclohexanone (compound 1114).

Procedure A was followed using3-(3-trifluoromethylphenyl)amino-cyclohexanone (125 mg) and(+)-(R)-1-naphthalen-1-yl-ethylamine. Chromatography (PE-EtOAc-MeOH100:0:0 to 0:100:0 to 0:90:10) afforded the title compound. LC-MS(method B): RT=2.94, [M+H]⁺=413.2.

Example 634-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexylamino]-benzonitrile(compound 1067)

General procedure G was followed using 4-amino-benzonitrile (1.18 g) andcyclohex-2-en-1-one. Chromatography (PE-EtOAc 100:0 to 0:100) afforded4-(3-oxo-cyclohexylamino)-benzonitrile.

Procedure A was followed using 4-(3-oxo-cyclohexylamino)-benzonitrile(145 mg) and (+)-(R)-1-naphthalen-1-yl-ethylamine. Chromatography(PE-EtOAc-MeOH 100:0:0 to 0:100:0 to 0:90:10) afforded the titlecompound. LC-MS (method B): RT=2.56, [M+H]⁺=370.2.

Example 64(3-Morpholin-4-yl-cyclohexyl)-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1068)

To a stirred mixture of morpholine (3.7 mL) and cyclohex-2-en-1-one (3.4mL) in water (50 mL) was added Cu(OAc)₂.H₂O (350 mg). The mixture wasstirred at r.t. for 15 h and filtered. The filtrate was extracted withEtOAc. The combined extracts were washed with water and brine, driedover Na₂SO₄, filtered and concentrated in vacuo to afford a 1:1 mixtureof cyclohex-2-en-1-one and 3-morpholin-4-yl-cyclohexanone used withoutfurther purification.

General procedure A was followed using 3-morpholin-4-yl-cyclohexanone (1g, 50% pure, 5.4 mmol) and (+)-(R)-1-naphthalen-1-yl-ethylamine.Chromatography (EtOAc) afforded the title compound as dark yellow oil(mixture of 2 isomers ca 1:1). ¹³C NMR (75.5 MHz, DMSO) δ: 142.28,142.05, 133.47, 133.39, 130.92, 130.86, 128.58, 126.42, 126.38, 125.61,125.57, 125.51, 125.45, 125.12, 123.21, 123.07, 122.97, 122.72, 66.41,66.30, 57.86, 57.78, 50.54, 49.54, 49.45, 49.35, 49.19, 48.46, 34.44,32.62, 30.84, 27.75, 27.64, 24.43, 19.68, 19.48.

Example 65((R)-1-Naphthalen-1-yl-ethyl)-(3-pyridin-2-yl-cyclohexyl)-amine(compounds 1069/1070)

General procedure A was followed using 3-(2-pyridinyl)cyclohexanone (1g) and (+)-(R)-1-naphthalen-1-yl-ethylamine. Chromatography(PE-EtOAc-MeOH 100:0:0 to 0:100:0 to 0:85:15) afforded the titlecompound as a mixture of 2 isomers (fraction A, compound 1069) and thetitle compound as a mixture of 2 isomers (fraction B, compound 1070) inthe ratio 1:1. Compound 1069, major isomer ¹³C NMR (75.5 MHz, DMSO) δ:165.48, 148.61, 142.04, 136.19, 133.47, 130.90, 128.62, 126.49, 125.69,125.56, 125.18, 123.02, 122.93, 121.17, 120.95, 50.37, 49.48, 39.02,37.25, 31.80, 28.94, 24.35, 20.03. Compound 1070 ¹³C NMR (75.5 MHz,DMSO) δ: 165.47, 165.39, 149.12, 142.64, 142.57, 136.83, 133.90, 133.88,131.23, 129.02, 126.89, 126.08, 126.04, 125.60, 123.38, 123.33, 123.24,123.18, 121.61, 121.46, 121.40, 54.20, 54.06, 49.80, 49.62, 45.16,44.86, 34.01, 32.86, 32.52, 32.45, 25.16, 24.86, 24.81.

Example 665-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-thiophene-2-carboxylicacid ethyl ester (compound 1071)

General procedure A was followed using5-(3-oxo-cyclohexyl)-thiophene-2-carboxylic acid ethyl ester (1 g) and(+)-(R)-1-naphthalen-1-yl-ethylamine. Chromatography (PE-EtOAc-MeOH100:0:0 to 0:100:0 to 0:90:10) afforded the title compound as a mixtureof 3 isomers (fraction A) and 0.9 g of the title compound as a mixtureof 3 isomers (fraction B). LC-MS (method B): RT=2.98, [M+H]⁺=408.2.

Example 675-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-thiophene-2-carboxylicacid (compound 1072)

To a solution of5-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-thiophene-2-carboxylicacid ethyl ester (fraction A 0.6 g) in MeOH (30 mL) and water (10 mL)was added LiOH (5 eq.). The solution was stirred at reflux for 2 h. MeOHwas removed in vacuo and 4N aq. HCl was added until the precipitatepersisted. The solid was filtered, washed with water and dried in vacuoto afford the title compound. ¹³C NMR (150.9 MHz, DMSO) δ: Major isomer:163.41, 157.15, 140.77, 140.77, 133.43, 131.63, 130.71, 128.67, 126.84,125.88, 125.54, 125.32, 123.38, 123.21, 122.76, 50.23, 49.74, 38.46,33.49, 33.43, 28.64, 23.83, 19.87.

Example 685-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-furan-2-carboxylicacid ethyl ester (compound 1073)

General procedure A was followed using5-(3-oxo-cyclohexyl)-furan-2-carboxylic acid ethyl ester (1 g) and(+)-(R)-1-naphthalen-1-yl-ethylamine. Chromatography (PE-EtOAc-MeOH100:0:0 to 0:100:0 to 0:90:10) afforded the title compound. LC-MS(method B): RT=2.85, [M+H]⁺=392.3.

Example 695-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-furan-2-carboxylicacid (compound 1074a, compound 1074b and compound 1074c)

To a solution of5-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-furan-2-carboxylicacid ethyl ester (1.4 g) in MeOH (75 mL) and water (25 mL) was addedLiOH (5 eq.). The solution was stirred at reflux for 2 h. MeOH wasremoved in vacuo and 4N aq. HCl was added until acidic pH. The compoundwas extracted with EtOAc. The combined extracts were dried over MgSO₄,filtered and concentrated in vacuo to afford the title compound as anoff-white solid. 3 isomers ¹³C NMR (150.9 MHz, DMSO) δ: 162.64, 162.55,162.15, 160.16, 160.10, 159.94, 145.27, 144.84, 144.79, 133.40, 130.69,130.63, 130.49, 130.46, 128.74, 128.70, 128.67, 127.34, 127.29, 126.99,126.89, 126.20, 126.14, 126.02, 125.95, 125.63, 125.58, 125.51, 125.38,125.34, 123.40, 123.29, 123.14, 122.74, 122.71, 122.62, 117.11, 116.96,116.82, 106.11, 106.07, 105.59, 105.56, 53.25, 52.95, 49.83, 49.66,49.32, 49.16, 36.00, 35.56, 35.43, 34.98, 33.02, 31.64, 31.49, 31.40,30.51, 30.35, 30.15, 29.60, 28.73, 23.70, 23.57, 23.47, 22.93, 22.87,20.00, 19.68.

General Procedure H

To a solution or a suspension of acid (1 eq.) in DMF (1M) under argonwas added HOBt (1.2 eq.), EDAC (1.3 eq.), 4-methyl morpholine (2 eq.)and N-hydroxyamidine (1.2 eq.). The mixture was stirred at r.t.overnight. CDI (1.1 eq.) was added and the mixture was subjected tomicrowave irradiation (10 min., 150° C.). The mixture was cooled tor.t., added EtOAc, washed with water and brine, dried over Na₂SO₄,filtered and concentrated in vacuo. If necessary, purification wasperformed by continuous gradient flash chromatography.

Preparation 4:3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexanecarboxylic acid

To a solution of 3-oxo-1-cyclohexane carboxylic acid (1.8 g) in1,2-dichlorethane (60 mL) were added(+)-(R)-1-naphthalen-1-yl-ethylamine (2.2 g), glacial AcOH (1 eq., 0.75mL) and NaBH(OAc)₃ (1.5 eq., 4.1 g). The mixture was stirred at r.t. for48 h before removal of the solvent. The residue was treated with 1N NaOH(ca 100 mL) and pH was adjusted to 7 by addition of 4N HCl. The mixturewas brought to reflux. The solid formed upon cooling was filtered andwashed with boiling EtOH to afford the title compound as a fine powder.The filtrate was concentrated in vacuo. The residue was dissolved in hotMeCN and little MeOH. The solid formed upon cooling was filtered andwashed with MeCN to afford the title compound.

Example 70{3-[3-(4-Fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1075)

General procedure H was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexanecarboxylic acid(preparation 4, 110 mg) and 4-fluoro-N-hydroxy-benzamidine.Chromatography (PE-EtOAc 100:0 to 0:100) afforded the title compound.¹³C NMR (75.5 MHz, DMSO) δ: 183.55, 166.86, 164.24 (¹J_(CF)=249.1 Hz),142.45, 133.92, 131.30, 129.87, 129.75, 129.06, 126.91, 126.05(³J_(CF)=9.8 Hz), 125.60, 123.31, 123.28, 116.68 (²J_(CF)=21.9 Hz),50.33, 49.29, 35.45, 31.69, 30.00, 29.29, 24.78, 20.24.

Example 71((R)-1-Naphthalen-1-yl-ethyl)-{3-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclohexyl}-amine(compound 1076)

General procedure H was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexanecarboxylic acid(preparation 4, 110 mg) and 4-trifluoromethyl-N-hydroxy-benzamidine.Chromatography (PE-EtOAc 100:0 to 40:60) afforded the title compound.LC-MS (method B): RT=3.23, [M+H]⁺=466.2.

Example 72((R)-1-Naphthalen-1-yl-ethyl)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-amine(compound 1077)

General procedure H was followed using3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexanecarboxylic acid(preparation 4, 110 mg) and N-hydroxy-benzamidine. Chromatography(PE-EtOAc 100:0 to 40:60) afforded the title compound. LC-MS (method B):RT=2.93, [M+H]⁺=398.2.

Example 73 4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1078)

To a solution of4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid (ex.53, 1.1 g) in DMF (40 mL) was added CDI (0.6 g). The mixture was stirredat r.t. for 2 h before addition of aq. NH₃ (8 mL). The mixture wasstirred at r.t. overnight. Et₂O and water were added. After extractionthe organic phase was washed with water and brine, dried over MgSO₄,filtered and concentrated in vacuo to afford the title compound as foam.LC-MS (method B): RT=2.46, [M+H]⁺=373.3.

Example 74N-Benzyloxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1079)

General procedure B was followed using4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid (ex.53, 0.27 mmol) and O-benzylhydroxylamine; hydrochloride. Chromatography(PE-EtOAc 50:50 to 33:67) afforded the title compound. LC-MS (method B):RT=3.03, [M+H]⁺=479.4.

Example 75 4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid 4-iodo-phenyl ester (compound 1080)

To a solution of4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid (ex.53, 0.4 g) in DMF (10 mL) was added CDI (0.21 g, 1.2 eq.). The solutionwas stirred at r.t. for 1 h before addition of 4-iodophenol (0.33 g, 1.4eq.) and K₂CO₃ (1.5 eq.). Stirring was continued at r.t. for 2 h. Waterwas added and the compound was extracted with EtOAc. The org. phase waswashed with water (3 times) and brine, concentrated in vacuo andpurified by chromatography (Heptane-EtOAc 100:0 to 60:40) to afford thetitle compound as an oil. LC-MS (method B): RT=4.15, [M+H]⁺=576.3.

General Procedure I

To a solution of4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid (ex.53, 1.6 g) in DMF (16 mL) was added CDI (0.83 g). The solution wasstirred at r.t. for 4.5 h, 0.3 mL of this solution was added to an amine(2 eq.). If the amine was furnished as hydrochloride DIPEA (1 eq.) wasadded. The mixture was shaken at r.t. for 3 days, filtered and purifiedby preparative HPLC-MS (re-analysed by LC/MS method A).

Example 762-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-ethanesulfonic acid (compound 1081)

General procedure I was followed using 2-amino-ethanesulfonic acid. ¹HNMR (600 MHz, DMSO) δ_(H) 8.86 (bs, 2H), 8.44 (t, 1H), 8.34 (d, 1H),7.92-8.07 (m, 2H), 7.80-7.90 (m, 1H), 7.68 (d, 2H), 7.54-7.66 (m, 3H),7.22 (d, 2H), 5.47 (bs, 1H), 3.52 (m, 2H), 3.13-3.23 (m, 1H), 3.02-3.11(m, 1H), 2.68 (t, 2H), 1.73-2.02 (m, 5H), 1.42-1.71 (m, 6H). LC-MS(method A): RT=4.14, [M+H]⁺=480.8, [M−H]⁻=478.7.

Example 77N—((R)-1-Hydroxymethyl-propyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide (compound 1082)

General procedure I was followed using (R)-2-amino-1-butanol. LC-MS(method A): RT=3.99, [M+H]⁺=444.8.

Example 78N—((S)-1-Hydroxymethyl-propyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide (compound 1083)

General procedure I was followed using (S)-2-amino-1-butanol. LC-MS(method A): RT=3.99, [M+H]⁺=444.8.

Example 79N-(2-Cyano-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1084)

General procedure I was followed using 2-cyano-ethylamine. LC-MS (methodA): RT=4.01, [M+H]⁺=426.4.

Example 80N-(2-Morpholin-4-yl-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1085)

General procedure I was followed using 2-morpholin-4-yl-ethylamine.LC-MS (method A): RT=3.49, [M+H]⁺=486.1.

Example 81N-(2-Fluoro-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1086)

General procedure I was followed using 2-fluoroethylamine;hydrochloride. LC-MS (method A): RT=4.04, [M+H]⁺=418.8.

Example 82N-(2,2-Difluoro-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1087)

General procedure I was followed using 2,2-difluoroethylamine. LC-MS(method A): RT=4.16, [M+H]⁺=437.1.

Example 833-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic acid methyl ester (compound 1088)

General procedure I was followed using 3-amino-propionic acid methylester; hydrochloride. ¹³C NMR (151 MHz, DMSO) δ 171.72, 166.11, 163.16,150.02, 133.46, 131.78, 130.69, 128.73, 127.08, 126.45, 126.03, 125.57,125.46, 123.49, 122.81, 51.32, 50.90, 50.69, 37.20, 36.63, 35.36, 33.53,32.48, 28.18, 23.59, 20.01. LC-MS (method A): RT=4.07, [M+H]⁺=459.0.

Example 84N-Methyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-N-pyridin-4-ylmethyl-benzamide(compound 1089)

General procedure I was followed using methyl-pyridin-4-ylmethyl-amine.LC-MS (method A): RT=3.64, [M+H]⁺=477.9.

Example 85N-(2-Dimethylamino-ethyl)-N-methyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1090)

General procedure I was followed using N,N,N′-trimethyl ethylenediamine.LC-MS (method A): RT=3.49, [M+H]⁺=458.2, [M−H]⁻=456.0.

Example 86(2-Hydroxymethyl-pyrrolidin-1-yl)-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone (compound 1091)

General procedure I was followed using (S)-pyrrolidin-2-yl-methanol.LC-MS (method A): RT=3.99, [M+H]⁺=456.8.

Example 87N-(2-Acetylamino-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1092)

General procedure I was followed using N-(2-amino-ethyl)-acetamide.LC-MS (method A): RT=3.86, [M+H]⁺=458.2.

Example 88N-Ethyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1093)

General procedure I was followed using ethylamine; hydrochloride. LC-MS(method A): RT=3.97, [M+H]⁺=400.8.

Example 89N-(2-Hydroxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1094)

General procedure I was followed using 2-hydroxy-ethylamine. LC-MS(method A): RT=3.82, [M+H]⁺=417.4.

Example 90N-(2-Hydroxy-1-hydroxymethyl-1-methyl-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1095)

General procedure I was followed using2-amino-2-methyl-propane-1,3-diol. LC-MS (method A): RT=3.86,[M+H]⁺=460.9.

Example 91N-(2-Methoxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1096)

General procedure I was followed using 2-methoxy-ethylamine. LC-MS(method A): RT=3.99, [M+H]⁺=430.8.

Example 92N-(2-Mercapto-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1097)

General procedure I was followed using 2-mercapto-ethylamine. LC-MS(method A): RT=4.11, [M+H]⁻=432.0.

Example 93 {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-acetic acid ethyl ester (compound 10981

General procedure I was followed using amino-acetic acid ethyl ester;hydrochloride. ¹H NMR (600 MHz, DMSO) δ 8.80 (t, 1H), 8.35 (d, 1H), 7.93(d, 1H), 7.77 (dd, 2H), 7.70 (d, 2H), 7.55-7.47 (m, 3H), 7.11 (d, 2H),4.73-4.65 (m, 1H), 4.11 (q, 2H), 3.96 (d, 2H), 3.02 (t, 1H), 2.88 (s,1H), 1.92-1.82 (m, 1H), 1.80-1.70 (m, 2H), 1.67-1.60 (m, 1H), 1.54-1.37(m, 6H), 1.34-1.26 (m, 1H), 1.20 (t, 3H). LC-MS (method A): RT=4.12,[M+H]⁺=458.9.

Example 94N,N-Dimethyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1099)

General procedure I was followed using dimethylamine. LC-MS (method A):RT=4.02, [M+H]⁺=400.8, [M−H]⁻=399.3.

Example 95N-(2-Hydroxy-ethyl)-N-methyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1100)

General procedure I was followed using 2-methylamino-ethanol. LC-MS(method A): RT=3.87, [M+H]⁺=431.4.

Example 96 N-Ethyl-N-(2-hydroxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide (compound 1101)

General procedure I was followed using 2-ethylamino-ethanol. LC-MS(method A): RT=3.96, [M+H]⁺=444.9.

Example 97 N,N-Bis-(2-hydroxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide (compound 1102)

General procedure I was followed using diethanol amine. LC-MS (methodA): RT=3.79, [M+H]⁺=460.9.

Example 98 N-(2-Dimethylamino-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide (compound 1103)

General procedure I was followed using N,N-(2-dimethylamino-ethyl)amine.LC-MS (method A): RT=3.47, [M+H]⁺=444.2.

Example 99 N-(3-Dimethylamino-propyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide (compound 1104)

General procedure I was followed usingN,N-(3-dimethylamino-propyl)amine. LC-MS (method A): RT=3.49,[M+H]⁺=358.0.

Example 100{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-Phenyl}-piperidin-1-yl-methanone(compound 1105)

General procedure I was followed using piperidine. LC-MS (method A):RT=4.27, [M+H]⁺=441.1.

Example 101 (4-Methyl-piperazin-1-yl)-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone (compound 1106)

General procedure I was followed using 4-methyl-piperazine. LC-MS(method A): RT=3.46, [M+H]⁺=456.2, [M−H]⁻=454.0.

Example 102[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-{4-[3-((R)-1-naphthalen-1yl-ethylamino)-cyclohexyl]-phenyl}-methanone(compound 1107)

General procedure I was followed using 2-hydroxy-ethyl)-piperazine.LC-MS (method A): RT=3.44, [M+H]⁺=486.1.

Example 103Morpholin-4-yl-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone (compound 1108)

General procedure I was followed using morpholine. LC-MS (method A):RT=4.02, [M+H]⁻=443.3.

Example 104(4-Hydroxy-piperidin-1-yl)-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone (compound 1109)

General procedure I was followed using piperidin-4-ol. LC-MS (method A):RT=3.87, [M+H]⁺=456.9.

Example 105 N-(3-Imidazol-1-yl-propyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide (compound 1110)

General procedure I was followed using 3-imidazol-1-yl-propylamine.LC-MS (method A): RT=3.51, [M+H]⁺=481.3.

General Procedure J.

To a solution/suspension of ester (6.5 mmol) in MeOH (30 mL) and water(10 mL) was added LiOH (5-8 eq.). After shaking/stirring for 4 h, thereaction mixture was concentrated slightly in vacuo, and additionalwater was added. The product was precipitated by adding 4N aq. HCl withstirring until pH 5 (to form the neutral compound) or pH 1-2 (to formthe hydrochloride salt). Precipitates were collected by filtration. Ifno precipitation occurred, the mixture was extracted with DCM, theorganic extracts were concentrated in vacuo, the residue was dissolvedin DMSO and/or DMF, and the product was purified by preparative HPLC-MS,re-analyzed by LC/MS (method B).

Example 106{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-aceticacid (compound 1115)

General procedure J was followed using{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-acetic acid ethyl ester (compound 1098). ¹³C NMR (151 MHz, DMSO)δ 171.29, 166.16, 149.98, 133.41, 131.32, 130.61, 128.71, 127.29,127.14, 126.48, 126.10, 125.53, 125.49, 123.58, 122.72, 50.78, 41.12,36.76, 36.50, 32.26, 27.88, 23.25, 19.91.

Example 107(S)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-succinicacid 4-tert-butyl ester 1-methyl ester (compound 1116)

General procedure I was followed using L-aspartic acid 4-tert-butyl1-methyl ester hydrochloride. ¹³C NMR (151 MHz, DMSO) δ 171.28, 169.04,165.91, 151.20, 142.43, 133.45, 130.89, 130.80, 128.58, 127.17, 126.49,126.39, 125.60, 125.53, 125.14, 123.08, 122.95, 80.25, 52.04, 51.12,50.16, 49.15, 38.54, 36.92, 36.81, 32.98, 28.95, 27.53, 24.62, 20.21.

Example 108(S)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-succinicacid 4-tert-butyl ester (compound 1117)

General procedure was followed using2-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-succinicacid 4-tert-butyl ester 1-methyl ester (compound 1116). ¹³C NMR (151MHz, DMSO) δ 172.79, 169.88, 165.42, 150.58, 141.95, 133.45, 131.72,130.79, 128.61, 126.97, 126.54, 126.44, 125.68, 125.55, 125.20, 123.16,122.91, 79.56, 51.01, 50.21, 50.18, 38.29, 37.80, 36.83, 32.89, 28.79,27.59, 24.38, 20.18.

Example 109(R)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionicacid methyl ester (compound 1118)

General procedure I was followed using D-phenylalanine methyl esterhydrochloride.

¹³C NMR (151 MHz, DMSO) δ 172.14, 166.19, 151.07, 142.42, 137.65,133.44, 130.94, 130.80, 128.93, 128.58, 128.11, 127.20, 126.41 (twooverlaying signals), 126.34, 125.61, 125.53, 125.14, 123.07, 122.94,54.07, 51.80, 51.06, 50.11, 38.56, 36.91, 36.07, 32.94, 28.93, 24.61,20.20.

Example 110(R)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionicacid (compound 1119)

General procedure J was followed using2-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionicacid methyl ester (compound 1118) and LiOH. ¹³C NMR (151 MHz, DMSO) δ172.53, 164.74, 150.30, 142.39, 139.34, 133.44, 132.53, 130.81, 129.40,128.57, 127.47, 126.50, 126.46, 126.40, 125.60, 125.54, 125.43, 125.14,123.06, 122.94, 55.49, 50.98, 50.05, 38.64, 37.00, 36.84, 32.94, 28.90,24.57, 20.21.

Example 111(S)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionicacid methyl ester (compound 1120)

General procedure I was followed using L-phenylalanine methyl esterhydrochloride. ¹³C NMR (75 MHz, DMSO) δ 172.12, 166.17, 151.06, 142.33,137.64, 133.45, 130.95, 130.80, 128.92, 128.58, 128.11, 127.20, 126.42,126.34, 125.60, 125.52, 125.15, 123.09, 122.94, 54.06, 51.79, 51.07,50.17, 38.43, 36.91, 36.09, 32.99, 28.94, 24.54, 20.20.

Example 112(S)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionicacid; hydrochloride (compound 1121)

General procedure J was followed using2-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionicacid methyl ester (compound 1120). ¹³C NMR (151 MHz, DMSO) δ 173.05,165.96, 148.84, 138.22, 133.31, 131.49, 130.29, 129.35, 128.96, 128.84,128.18, 128.01, 127.29, 126.71, 126.42, 126.16, 125.85, 125.48, 124.57,122.39, 54.14, 51.40, 50.43, 36.28, 36.11, 35.86, 31.35, 26.28, 21.73,19.47.

Example 113(S)-3-(1H-Indol-3-yl)-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid methyl ester (compound 1122)

General procedure I was followed using L-tryptophan methyl esterhydrochloride. ¹³C NMR (151 MHz, DMSO) δ 172.49, 166.18, 151.06, 142.42,135.97, 133.44, 130.98, 130.80, 128.58, 127.24, 126.94, 126.39, 125.60,125.53, 125.14, 123.50, 123.07, 122.94, 120.86, 118.30, 117.88, 111.35,109.88, 53.60, 51.76, 51.08, 50.14, 38.50, 36.92, 33.02, 28.93, 26.48,24.60, 20.20.

Example 114(S)-3-(1H-Indol-3-yl)-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid (compound 1123)

General procedure J was followed using3-(1H-indol-3-yl)-2-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid methyl ester (compound 1122).

¹³C NMR (151 MHz, DMSO) δ 172.45, 164.74, 150.15, 142.39, 135.66,133.44, 132.79, 130.80, 128.58, 128.18, 127.24, 126.50, 126.38, 125.59,125.54, 125.13, 123.15, 123.07, 122.94, 120.16, 118.67, 117.60, 111.57,110.77, 55.29, 51.02, 50.09, 38.58, 36.83, 33.00, 28.92, 27.07, 24.57,20.21.

Example 115(R)-3-(1H-Indol-3-yl)-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid methyl ester (compound 1124)

General procedure I was followed using D-tryptophan methyl esterhydrochloride. ¹³C NMR (151 MHz, DMSO) δ 172.48, 166.21, 151.04, 142.41,135.98, 133.44, 130.99, 130.80, 128.58, 127.24, 126.95, 126.38, 125.60,125.53, 125.14, 123.50, 123.07, 122.94, 120.86, 118.30, 117.89, 111.35,109.90, 53.63, 51.76, 51.07, 50.12, 38.55, 36.91, 32.97, 28.93, 26.48,24.60, 20.21.

Example 116(R)-3-(1H-Indol-3-yl)-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid (compound 1125)

General procedure J was followed using3-(1H-indol-3-yl)-2-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid methyl ester (compound 1124). ¹³C NMR (151 MHz, DMSO) δ 172.04,165.45, 150.47, 142.31, 135.83, 133.44, 132.05, 130.80, 128.58, 127.60,126.86, 126.42, 126.35, 125.61, 125.53, 125.14, 123.24, 123.07, 122.93,120.49, 118.33, 117.92, 111.04, 54.47, 50.95, 50.08, 38.54, 36.84,32.96, 28.87, 26.88, 24.54, 20.20.

General Procedure I-1:

To a solution of4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid(compound 1056, 35 mg) in DMF (1 mL) was added HATU (1.2 eq.) and DIPEA(2 eq). The solution was stirred at r.t. for 2 h, then added to an amine(2 eq.). If the amine was furnished as hydrochloride DIPEA (2 eq.) wasadded. The mixture was shaken at r.t. overnight, filtered and purifiedby preparative HPLC-MS (re-analysed by LC/MS method A).

General Procedure I-2:

Similar to procedure I, except that compound 1057 (Example 54) was usedinstead of compound 1056

General Procedure I-3

To a solution or a suspension of4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid(compound 1056) in DMF (1M) under argon was added HOBt (1.1 eq.), EDAC(1 eq.), 4-methyl morpholine (1 eq.) and an amine (1 eq.). The mixturewas stirred at r.t. overnight. DMF was removed in vacuo, andpurification was performed by continuous gradient flash chromatography.

Example 117(Cyclohexyl-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-aceticacid ethyl ester (compound 1126)

General procedure I-2 was followed using N-cyclohexylglycine ethylester. ¹H NMR (500 MHz, DMSO, T=400 K) δ 8.31 (d, 1H), 7.87 (d, 1H),7.74 (d, 1H), 7.69 (d, 1H), 7.50-7.42 (m, 3H), 7.20 (dd, 4H), 4.81-4.67(m, 1H), 4.09 (q, 2H), 3.99 (s, 2H), 3.76-3.63 (m, 1H), 3.08 (t, 1H),2.97-2.87 (m, 1H), 1.90-1.83 (m, 1H), 1.81-1.67 (m, 6H), 1.65-1.37 (m,11H), 1.18 (t, 3H), 1.14-1.02 (m, 3H). LC-MS (method A): RT=5.47,[M+H]⁺=541.3.

Example 1182-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-malonicacid diethyl ester (compound 1127)

General procedure I-2 was followed using diethyl aminomalonatehydrochloride. ¹H NMR (500 MHz, DMSO) δ 8.45 (s, 1H), 8.28 (d, 1H), 7.90(d, 1H), 7.79 (d, 1H), 7.76-7.69 (m, 3H), 7.55-7.44 (m, 3H), 7.25 (d,2H), 5.25 (d, 1H), 4.98-4.78 (m, 1H), 4.27-4.14 (m, 4H), 3.18-3.08 (m,1H), 3.05-2.97 (m, 1H), 1.88 (m, 1H), 1.61 (m, 10H), 1.23 (t, 6H).

Example 119(S)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid tert-butyl ester (compound 1128)

General procedure I-3 was followed using L-serine tert-butyl esterhydrochloride. ¹³C NMR (151 MHz, DMSO) δ 169.55, 166.25, 150.81, 133.45,131.32, 130.78, 128.61, 127.22, 126.55, 126.42, 125.68, 125.54, 125.20,123.15, 122.92, 80.43, 61.20, 56.10, 51.06, 50.28, 38.33, 36.86, 32.88,28.80, 27.61, 24.40, 20.17.

Example 1205-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-nicotinicacid (compound 1129)

General procedure I-1 was followed using 5-amino-nicotinic acid ethylester. ¹H NMR (600 MHz, DMSO) δ 9.12 (d, 1H), 8.79 (d, 1H), 8.74-8.70(m, 1H), 8.36 (d, 1H), 7.94 (d, 1H), 7.85 (d, 2H), 7.80 (dd, 2H),7.57-7.48 (m, 3H), 7.22 (d, 2H), 4.86-4.76 (m, 1H), 3.12-3.04 (m, 1H),2.97-2.90 (m, 1H), 1.95-1.30 (m, 11H).

Example 1214-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-benzoicacid (compound 1130)

General procedure I-1 was followed using 4-amino-benzoic acid ethylester. The intermediate ethyl ester was hydrolyzed following generalprocedure J to afford the title compound. ¹H NMR (600 MHz, DMSO) δ 10.41(s, 1H), 8.35 (d, 1H), 7.97-7.88 (m, 5H), 7.86-7.77 (m, 4H), 7.59-7.50(m, 3H), 7.22 (d, 2H), 4.84 (br s, 1H), 3.11-3.04 (m, 1H), 3.02-2.92 (m,1H), 1.92-1.32 (m, 11H).

Example 1224-Methoxy-3-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-benzoicacid methyl ester hydrochloride (compound 1131)

General procedure I-1 was followed using methyl3-amino-4-methoxybenzoate. The product was dissolved in ethyl acetateand treated with HCl in dioxane (4 M) and diethyl ether. The precipitatewas filtered to afford the title compound. ¹H NMR (600 MHz, DMSO) δ 9.48(s, 1H), 8.85 (m, 2H), 8.42 (d, 1H), 8.35 (d, 1H), 8.03 (t, 2H), 7.89(d, 3H), 7.83 (dd, 1H), 7.69-7.59 (m, 3H), 7.31 (d, 2H), 7.23 (d, 1H),5.55 (s, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.30-3.22 (m, 1H), 3.16-3.07(m, 1H), 2.04-1.77 (m, 5H), 1.72 (d, 3H), 1.70-1.60 (m, 2H), 1.56-1.49(m, 1H).

Example 1232-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-benzoicacid hydrochloride (compound 1132)

General procedure I-1 was followed using methyl 2-aminobenzoate. Theintermediate methyl ester was hydrolyzed following general procedure Jto afford the title compound. ¹H NMR (600 MHz, DMSO) δ 8.69 (d, 1H),8.35 (d, 1H), 8.06 (dd, 1H), 8.00 (dd, 2H), 7.90 (d, 3H), 7.67-7.62 (m,2H), 7.59 (t, 1H), 7.56-7.49 (m, 1H), 7.34 (d, 2H), 7.12 (t, 1H),5.53-5.34 (m, 1H), 3.24-3.18 (m, 1H), 3.18-3.11 (m, 1H), 2.00-1.76 (m,5H), 1.73-1.48 (m, 6H).

Example 124(Carboxymethyl-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-aceticacid hydrochloride (compound 1133)

General procedure I-1 was followed using diethyl iminodiacetate. Theintermediate diethyl ester was hydrolyzed following general procedure Jto afford the title compound. ¹H NMR (600 MHz, DMSO) δ 8.34 (d, 1H),8.00 (d, 1H), 7.96 (d, 1H), 7.84 (d, 1H), 7.62 (t, 2H), 7.58 (t, 1H),7.24 (d, 2H), 7.17 (d, 2H), 5.36 (s, 1H), 4.00 (s, 2H), 3.79 (s, 2H),3.18-3.13 (m, 1H), 3.06-2.99 (m, 1H), 1.92-1.74 (m, 5H), 1.65 (d, 3H),1.60-1.46 (m, 3H).

Example 1251-({4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-methyl)-cyclopentanecarboxylicacid (compound 1134)

General procedure I-1 was followed using ethyl1-(aminomethyl)-cyclopentanecarboxylate. The intermediate ethyl esterwas hydrolyzed following general procedure J to afford the titlecompound. ¹H NMR (600 MHz, DMSO) δ 8.34 (d, 1H), 8.15 (d, 1H), 7.93 (d,1H), 7.77 (dd, 2H), 7.64 (d, 2H), 7.55-7.48 (m, 3H), 7.10 (d, 2H), 4.70(q, 1H), 3.48 (d, 2H), 3.06-2.98 (m, 1H), 2.89-2.85 (m, 1H), 1.95-1.82(m, 3H), 1.81-1.70 (m, 2H), 1.68-1.46 (m, 10H), 1.46-1.36 (m, 1H), 1.44(d, 3H), 1.35-1.26 (m, 1H).

Example 1261-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-cyclopentanecarboxylicacid hydrochloride (compound 1135)

General procedure I-1 was followed using methyl1-amino-1-cyclopentane-carboxylate hydrochloride. The intermediatemethyl ester was hydrolyzed following general procedure J to afford thetitle compound. ¹H NMR (600 MHz, DMSO) δ 11.93 (br s, 1H), 8.88 (s, 2H),8.42 (s, 1H), 8.34 (d, 1H), 8.01 (dd, 2H), 7.89 (d, 1H), 7.77 (d, 2H),7.69-7.63 (m, 2H), 7.61 (t, 1H), 7.23 (d, 2H), 5.54 (br s, 1H),3.27-3.20 (m, 1H), 3.12-3.05 (m, 1H), 2.18-2.09 (m, 2H), 2.06-1.57 (m,16H), 1.54-1.46 (m, 1H).

Example 1273-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid hydrochloride (compound 1136)

General procedure J was followed using3-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionic acid methyl ester (compound 1088). ¹H NMR (600 MHz,DMSO) δ 9.47 (br s, 1H), 8.46 (t, 1H), 8.35 (d, 1H), 7.97 (d, 1H), 7.89(d, 1H), 7.72 (d, 2H), 7.60-7.52 (m, 3H), 7.18 (d, 2H), 5.15 (br s, 1H),3.45 (dd, 2H), 3.20-3.11 (m, 1H), 3.06-2.98 (m, 1H), 2.54-2.48 (m, 2H)(overlaying DMSO signal), 2.00-1.81 (m, 3H), 1.79-1.58 (m, 5H),1.57-1.36 (m, 3H).

Example 128(1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-cyclohexyl)-aceticacid hydrochloride (compound 1137)

General procedure I-1 was followed using (1-amino-cyclohexyl)-aceticacid methyl ester. The intermediate methyl ester was hydrolyzedfollowing general procedure J to afford the title compound. ¹H NMR (600MHz, DMSO) δ 12.94-10.67 (br s, 1H), 8.83 (s, 2H), 8.34 (d, 1H), 8.02(dd, 2H), 7.89 (d, 1H), 7.70 (d, 2H), 7.68-7.64 (m, 2H), 7.61 (t, 1H),7.47 (s, 1H), 7.20 (d, 2H), 5.59-5.50 (m, 1H), 3.30-3.20 (m, 1H),3.11-3.03 (m, 1H), 2.75 (s, 2H), 2.32 (m, 2H), 2.02-1.86 (m, 3H),1.85-1.74 (m, 2H), 1.72 (d, 3H), 1.68-1.57 (m, 2H), 1.57-1.41 (m, 8H),1.30-1.20 (m, 1H).

Example 1291-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-cyclopropanecarboxylicacid ethyl ester (compound 1138)

General procedure I was followed using 1-aminocyclopropane-1-carboxylicacid ethyl ester hydrochloride. ¹³C NMR (151 MHz, DMSO) δ 172.07,167.00, 151.01, 142.43, 133.45, 131.26, 130.81, 128.59, 127.16, 126.40,125.60, 125.54, 125.15, 123.08, 122.95, 60.43, 60.13, 51.10, 50.17,38.57, 36.92, 33.25, 33.00, 28.96, 24.62, 20.22, 17.49, 16.62, 13.98.

Example 1301-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-cyclopronanecarboxylicacid (compound 11391

General procedure J was followed using1-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-cyclopropanecarboxylicacid ethyl ester (compound 1138). ¹³C NMR (151 MHz, DMSO) δ 174.06,167.01, 150.30, 133.58, 131.68, 130.79, 128.88, 127.45, 127.41, 126.59,126.53, 126.24, 125.71, 125.63, 123.77, 122.91, 51.00, 50.89, 36.68,33.34, 33.15, 32.56, 28.15, 23.60, 20.10, 17.01, 16.57.

Example 1311-({4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-methyl)-cyclopropanecarboxylicacid (compound 1140)

General procedure I-1 was followed using1-(aminomethyl)-cyclopropane-carboxylic acid ethyl ester. Theintermediate ethyl ester was hydrolyzed following general procedure J toafford the title compound. ¹H NMR (600 MHz, DMSO) δ 8.35 (d, 1H), 8.21(t, 1H), 7.93 (d, 1H), 7.80 (d, 1H), 7.77 (d, 1H), 7.67 (d, 2H), 7.52(dq, 3H), 7.10 (d, 2H), 4.76 (br s, 1H), 3.52 (d, 2H), 3.06-2.97 (m,1H), 2.93-2.87 (m, 1H), 1.91-1.81 (m, 1H), 1.80-1.70 (m, 2H), 1.69-1.62(m, 1H), 1.58-1.38 (m, 6H), 1.37-1.28 (m, 1H), 1.02 (q, 2H), 0.89 (dd,2H).

Example 1322-Methyl-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid (compound 1141)

General procedure I-1 was followed using 2-methylalanine methyl esterhydrochloride. The intermediate methyl ester was hydrolyzed followinggeneral procedure J to afford the title compound. ¹H NMR (300 MHz, DMSO)δ 8.35 (d, 1H), 8.31 (s, 1H), 7.98-7.89 (m, 1H), 7.82 (dd, 2H), 7.69 (d,2H), 7.59-7.46 (m, 3H), 7.11 (d, 2H), 4.83 (q, 1H), 3.13-2.99 (m, 1H),2.97-2.88 (m, 1H), 1.97-1.21 (m, 8H), 1.50 (d, 3H), 1.44 (s, 6H).

Example 1331-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-azetidine-3-carboxylicacid (compound 1142)

General procedure I-1 was followed using 3-azetidinecarboxylic acidmethyl ester hydrochloride. The intermediate methyl ester was hydrolyzedfollowing general procedure J to afford the title compound. ¹H NMR (600MHz, DMSO) δ 8.34 (d, 1H), 7.97-7.91 (m, 1H), 7.81 (d, 1H), 7.77 (d,1H), 7.53 (m, 3H), 7.48 (d, 2H), 7.13 (d, 2H), 4.82 (br s, 1H), 4.43 (m,1H), 4.31 (m, 1H), 4.19 (m, 1H), 4.04 (m, 1H), 3.43 (m, 1H), 3.02 (m,1H), 2.90 (m, 1H), 1.90-1.65 (m, 4H), 1.61-1.30 (m, 7H).

Example 134(Methyl-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-aceticacid (compound 1143)

General procedure I-1 was followed using n-methylglycine ethyl esterhydrochloride. The intermediate ethyl ester was hydrolyzed followinggeneral procedure J to afford the title compound. ¹H NMR (600 MHz, DMSO)δ 8.34 (d, 1H), 7.94 (d, 1H), 7.82 (d, 1H), 7.79-7.74 (m, 1H), 7.57-7.48(m, 3H), 7.27 (d, 1H), 7.12 (dt, 3H), 4.91-4.76 (br s, 1H), 4.11 (s,1H), 3.89 (s, 1H), 3.06-2.98 (m, 1H), 2.97-2.90 (m, 4H), 1.91-1.67 (m,4H), 1.63-1.53 (m, 1H), 1.53-1.40 (m, 5H), 1.40-1.30 (m, 1H).

Example 1354-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-butyricacid (compound 1144)

General procedure I-1 was followed using ethyl 4-aminobutyratehydrochloride. The intermediate ethyl ester was hydrolyzed followinggeneral procedure J to afford the title compound. ¹H NMR (600 MHz, DMSO)δ 8.35 (t, 2H), 7.97-7.91 (m, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.68 (d,2H), 7.53 (m, 3H), 7.10 (d, 2H), 4.79 (s, 1H), 3.24 (dd, 2H), 3.02 (t,1H), 2.92 (s, 1H), 2.25 (t, 2H), 1.73 (t, 2H), 1.92-1.63 (m, 4H),1.60-1.29 (m, 7H).

Example 1361-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-piperidine-4-carboxylicacid ethyl ester (compound 1145)

General procedure I-1 was followed using 4-piperidinecarboxylic acidethyl ester. ¹³C NMR (126 MHz, DMSO) δ 173.69, 169.04, 148.70, 142.38,133.45, 133.30, 130.83, 128.57, 126.60, 126.51, 126.40, 125.60, 125.52,125.13, 123.04, 122.93, 59.87, 50.93, 50.00, 46.26, 39.92, 38.67, 36.85,32.98, 28.93, 27.84, 24.50, 20.24, 13.96.

Example 1371-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-piperidine-4-carboxylicacid (compound 1146)

General procedure J was followed using1-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-piperidine-4-carboxylicacid ethyl ester (compound 1145). ¹H NMR (600 MHz, DMSO) δ 12.21 (br s,1H), 9.37 (d, 2H), 8.35 (d, 1H), 8.13 (d, 1H), 7.99 (dd, 2H), 7.69-7.54(m, 3H), 7.25 (dd, 4H), 5.50 (s, 1H), 4.43-4.18 (m, 1H), 160-3.41 (m,1H), 3.24-3.12 (m, 2H), 3.11-2.79 (m, 2H), 2.57-2.47 (m, 1H), 2.11-1.69(m, 10H), 1.68-1.38 (m, 5H).

Example 138(Cyclohexyl-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-aceticacid ethyl ester (compound 1147)

To a solution of4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid (ex.54, 20 mg) in 400 μL DMF were added diisopropyl ethyl amine (3 eq.) andbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP, 1 eq.).The solution was cooled in an ice bath, and N-cyclohexylglycine ethylester (3 eq.) was added followed by 1-hydroxy-7-azabenzotriazole (HOAt,3 eq.). After shaking overnight at r.t., the reaction mixture wasdiluted with aqueous NaHCO₃ and extracted with dichloromethane. Theorganic extracts were concentrated in vacuo and purified by HPLC-MS. ¹HNMR (500 MHz, DMSO) δ 825 (d, 1H), 7.98 (s, 2H), 7.82 (s, 1H), 7.59 (s,3H), 7.12 (t, 4H), 5.51-5.31 (m, 1H), 4.10 (q, 2H), 3.99 (s, 2H),3.69-3.57 (m, 1H), 3.36-3.22 (m, 1H), 3.20-3.10 (m, 1H), 2.10-1.95 (m,2H), 1.86-1.64 (m, 12H), 1.56-1.38 (m, 4H), 1.19 (t, 3H), 1.13-0.98 (m,3H).

Example 139(Cyclohexyl-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-aceticacid (compound 1148)

General procedure J was followed using(cyclohexyl-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-aceticacid ethyl ester (compound 1147).

LC-MS (method B): RT=3.23, [M+H]⁺=513.5

Example 1404-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-N—((R)-2-oxo-tetrahydro-furan-3-yl)-benzamide(compound 1149)

General procedure I was followed using (R)-(+)-2-amino-4-butyrolactonehydrochloride. ¹³C NMR (75 MHz, DMSO) δ 175.25, 165.82, 151.24, 142.45,133.46, 130.82, 130.77, 128.58, 127.08, 126.54, 126.41, 125.59, 125.53,125.14, 123.10, 122.97, 65.21, 51.16, 50.20, 48.23, 38.56, 36.92, 32.93,29.01, 27.90, 24.60, 20.23.

Example 141N-Cyanomethyl-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1150)

General procedure I was followed using amino acetonitrile hydrochloride.¹H NMR (300 MHz, DMSO) δ 9.08 (t, 1H), 8.35 (d, 1H), 7.97-7.87 (m, 1H),7.84-7.66 (m, 4H), 7.58-7.43 (m, 3H), 7.13 (d, 2H), 4.66 (s, 1H), 4.29(d, 2H), 3.12-2.96 (m, 1H), 2.94-2.82 (m, 1H), 1.95-1.21 (m, 12H).

Example 142N-(4-Cyano-1H-pyrazol-3-yl)-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1151)

General procedure I was followed using 4-cyano-5-aminopyrazole. ¹H NMR(300 MHz, DMSO) δ 8.35 (d, 1H), 8.02 (s, 1H), 7.96-7.70 (m, 6H),7.56-7.43 (m, 3H), 7.22-7.10 (m, 2H), 4.65 (q, 1H), 3.14-2.98 (m, 1H),2.90-2.81 (m, 1H), 2.23 (br s, 1H), 1.97-1.20 (m, 11H).

Example 143(R)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid benzyl ester (compound 1152)

General procedure I-3 was followed using D-serine benzyl esterhydrochloride. ¹H NMR (600 MHz, DMSO) δ 8.47 (d, 1H), 8.35 (d, 1H), 7.92(d, 1H), 7.76 (dd, 2H), 7.73 (d, 2H), 7.55-7.46 (m, 3H), 7.40-7.29 (m,5H), 7.11 (d, 2H), 5.15 (dd, 2H), 5.07 (t, 1H), 4.70-4.62 (m, 1H), 4.57(dd, 1H), 3.86-3.78 (m, 2H), 3.03 (t, 1H), 2.87 (s, 1H), 2.22 (br s,1H), 1.93-1.82 (m, 1H), 1.82-1.70 (m, 2H), 1.63 (d, 1H), 1.54-1.35 (m,6H), 1.29 (t, 1H).

Example 144(S)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid benzyl ester (compound 1153)

General procedure I-3 was followed using L-serine benzyl esterhydrochloride. ¹H NMR (600 MHz, DMSO) δ 8.47 (d, 1H), 8.35 (d, 1H), 7.92(d, 1H), 7.77 (dd, 2H), 7.73 (d, 2H), 7.55-7.46 (m, 3H), 7.39-7.29 (m,5H), 7.12 (d, 2H), 5.15 (dd, 2H), 5.07 (t, 1H), 4.66 (br s, 1H), 4.57(dt, 1H), 3.86-3.78 (m, 2H), 3.03 (t, 1H), 2.91-2.83 (m, 1H), 2.22 (brs, 1H), 1.94-1.83 (m, 1H), 1.81-1.70 (m, 2H), 1.67-1.59 (m, 1H),1.53-1.24 (m, 7H).

Example 145(S)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid methyl ester (compound 1154)

General procedure I-3 was followed using L-serine methyl esterhydrochloride. ¹³C NMR (126 MHz, DMSO) δ 171.12, 166.38, 151.16, 142.39,133.58, 131.16, 130.92, 128.71, 127.39, 126.58, 126.55, 125.75, 125.65,125.29, 123.24, 123.06, 61.09, 55.58, 51.84, 51.24, 50.36, 38.55, 37.03,33.07, 29.06, 24.62, 20.32.

Example 146(R)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid methyl ester (compound 1155)

General procedure I-3 was followed using D-serine methyl esterhydrochloride. ¹H NMR (600 MHz, DMSO) δ 8.43 (d, 1H), 8.35 (d, 1H), 7.93(d, 1H), 7.77 (dd, 2H), 7.74 (d, 2H), 7.56-7.46 (m, 3H), 7.12 (d, 2H),5.05 (t, 1H), 4.69 (s, 1H), 4.51 (dd, 1H), 3.78 (t, 2H), 3.64 (s, 3H),3.03 (m, 1H), 2.88 (s, 1H), 1.93-1.83 (m, 1H), 1.82-1.70 (m, 2H),1.68-1.60 (m, 1H), 1.54-1.46 (m, 2H), 1.46-1.35 (m, 1H), 1.44 (d, 3H),1.35-1.25 (m, 1H).

Example 147(S)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid ethyl ester hydrochloride (compound 1156)

General procedure I-3 was followed using L-serine ethyl esterhydrochloride. The product was dissolved in ethyl acetate and treatedwith HCl in dioxane (4 M) and diethyl ether. The precipitate wasfiltered to afford the title compound. ¹H NMR (300 MHz, DMSO) δ 9.42 (s,2H), 8.51 (d, 1H), 8.35 (d, 1H), 8.15 (d, 1H), 7.99 (t, 2H), 7.84 (d,2H), 7.61 (dt, 13.5, 3H), 7.28 (d, 2H), 5.57-5.43 (m, 1H), 5.24-4.99 (brs, 1H), 4.48 (dd, 1H), 4.11 (q, 2H), 3.80 (d, 2H), 3.31-3.08 (m, 2H),2.10-1.36 (m, 12H), 1.19 (t, 3H).

Example 1483-Hydroxy-2-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid hydrochloride (compound 1157)

(S)-3-Hydroxy-2-{4-[(1S,3S)-3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid tert-butyl ester (compound 1128, 150 mg) was suspended in 5 mL HCl(4M in dioxane) and stirred overnight at room temperature. Diethyletherwas added to the reaction mixture, and the precipitate thus formed wasfiltered off, washed with additional ether and dried. ¹³C NMR (151 MHz,DMSO) δ 171.84, 166.00, 148.26, 133.82, 133.34, 131.63, 130.23, 129.77,128.94, 127.50, 127.02, 126.43, 126.14, 125.52, 124.61, 122.30, 61.04,55.58, 51.97, 48.48, 35.74, 33.44, 30.97, 25.84, 20.79, 19.32.

Example 149(R)-4-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-butyricacid (compound 1158)

General procedure J was followed using4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-N-(2-oxo-tetrahydro-furan-3-yl)-benzamide(compound 1149). ¹³C NMR (75 MHz, DMSO) δ 173.97, 166.15, 150.61,141.77, 133.45, 131.49, 130.77, 128.61, 127.16, 126.60, 126.39, 125.70,125.53, 125.21, 123.18, 122.90, 57.67, 51.01, 50.27, 50.12, 38.18,36.83, 33.79, 32.87, 28.76, 24.28, 20.16.

Example 150N-tert-Butoxy-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamideformiate (compound 1159)

General procedure I was followed using O-(tert.-butyl)-hydroxylaminehydrochloride. ¹³C NMR (151 MHz, DMSO) δ 165.88, 163.70, 150.90, 142.24,133.44, 130.78, 130.22, 128.59, 127.10, 126.50, 126.45, 125.63, 125.53,125.16, 123.09, 122.92, 80.68, 51.00, 50.13, 38.43, 36.93, 32.99, 28.86,26.39, 24.52, 20.18.

Example 151N-tert-Butoxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamideformiate (compound 1160)

General procedure I-2 was followed using O-(tert.-butyl)-hydroxylaminehydrochloride. ¹³C NMR (151 MHz, DMSO) δ 165.89, 163.24, 150.59, 141.24,133.38, 130.75, 130.31, 128.62, 127.20, 126.66, 125.80, 125.52, 125.24,123.09, 122.71, 80.70, 50.03, 49.49, 36.60, 35.95, 32.93, 30.31, 26.40,24.01, 20.33.

Example 152N-Methoxy-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamideformiate (compound 1161)

General procedure I was followed using O-methyl-hydroxylaminehydrocloride. ¹³C NMR (75 MHz, DMSO) δ 163.56, 150.81, 141.06, 133.57,130.84, 129.75, 128.77, 126.99, 126.72, 125.97, 125.65, 125.44, 123.44,122.96, 63.18, 51.10, 50.60, 37.77, 36.87, 32.69, 28.59, 24.02, 20.18.

Example 153N-Methoxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamideformiate (compound 1162)

General procedure I-2 was followed using O-methyl-hydroxylaminehydrocloride. ¹³C NMR (151 MHz, DMSO) δ 163.43, 150.64, 140.70, 133.38,130.71, 129.65, 128.65, 126.94, 126.83, 126.76, 125.89, 125.52, 125.31,123.21, 122.69, 63.08, 50.05, 49.62, 36.52, 35.63, 32.71, 30.11, 23.77,20.27.

Example 1544-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-N-(tetrahydro-furan-3-ylmethoxy)-benzamide(compound 1163)

General procedure I was followed usingO-(tetrahydro-furan-3-ylmethyl)-hydroxylamine (WO 2005054179). ¹³C NMR(75 MHz, DMSO) δ 163.30, 150.95, 141.75, 133.47, 130.78, 129.63, 128.63,126.89, 126.61, 125.73, 125.54, 125.24, 123.19, 122.91, 77.10, 69.88,66.72, 51.05, 50.33, 38.13, 37.28, 36.88, 32.78, 28.78, 28.37, 24.27,20.15.

Example 1554-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-N-(tetrahydro-furan-3-ylmethoxy)-benzamide(compound 1164)

General procedure I-2 was followed usingO-(tetrahydro-furan-3-ylmethyl)-hydroxylamine (WO 2005054179). LC-MS(method B): RT=2.49, [M+H]⁺=473.3.

Example 156N-Methoxy-N-methyl-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide;bis formate (compound 1165)

General procedure I was followed using N,O-dimethylhydroxylaminehydrochloride. ¹H NMR (300 MHz, DMSO) δ 8.34 (d, 1H), 8.20 (s, 2H),7.97-7.88 (m, 1H), 7.76 (t, 2H), 7.57-7.39 (m, 5H), 7.09 (d, 8.2, 2H),4.69 (q, 1H), 3.53 (s, 3H), 3.22 (s, 3H), 3.09-2.95 (m, 1H), 2.91-2.82(m, 1H), 1.95-1.60 (m, 4H), 1.57-1.21 (m, 7H).

Example 157N-Methoxy-N-methyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1166)

General procedure I-2 was followed using N,O-dimethylhydroxylaminehydrochloride. ¹H NMR (300 MHz, DMSO) δ 8.34-8.27 (m, 1H), 7.96-7.88 (m,1H), 7.76 (dd, 2H), 7.56-7.43 (m, 5H), 7.24 (d, 2H), 4.77 (q, 1H), 3.54(s, 3H), 3.23 (s, 3H), 3.17-3.06 (m, 1H), 2.87-2.80 (m, 1H), 1.90-1.34(m, 11H).

Example 158N-Benzyloxy-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1167)

General procedure I was followed using O-benzyl-hydroxylaminehydrochloride. ¹³C NMR (75 MHz, DMSO) δ 163.90, 151.07, 141.88, 136.04,133.57, 130.89, 129.74, 128.86, 128.73, 128.30, 128.25, 127.03, 126.71,125.82, 125.65, 125.33, 123.31, 123.01, 76.92, 51.15, 50.40, 38.26,36.98, 32.89, 28.87, 24.39, 20.26.

Example 159N-Benzyloxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1168)

General procedure I-2 was followed using O-benzyl-hydroxylaminehydrochloride. ¹³C NMR (75 MHz, DMSO) δ 163.71, 150.20, 139.74, 135.94,133.41, 130.66, 129.73, 128.78, 128.71, 128.21, 128.17, 127.14, 127.01,126.72, 126.07, 125.53, 125.43, 123.46, 122.63, 76.83, 50.05, 49.89,36.39, 35.08, 32.39, 29.79, 23.35, 20.18.

Example 160N-Hydroxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1169)

To a solution ofN-benzyloxy-4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1168, 17 mg) in 700 μL were added 2 mg palladium on carbon(10%), and the mixture was hydrogenated with vigorous stirring overnightat r.t. The catalyst was filtered off through Celite and the filtratewas concentrated in vacuo. The product was purified by HPLC. ¹H NMR (600MHz, DMSO) δ 8.32 (d, 1H), 8.19 (s, 1H), 7.92 (dd, 1H), 7.78 (d, 1H),7.74 (d, 1H), 7.56 (d, 2H), 7.53-7.46 (m, 3H), 7.20 (d, 2H), 4.75 (q,1H), 3.11-3.05 (m, 1H), 2.83 (br s, 1H), 1.86-1.73 (m, 3H), 1.62-1.55(m, 1H), 1.51-1.35 (m, 7H).

Example 161N-Hydroxy-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1170)

4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid(compound 1056, 50 mg) was suspended in a 1:1 mixture of DMF and THF(each 150 μL) and cooled to −20° C. N-methyl morpholine (16 μL) andisobutyl chloroformate (18 μL) were added. The reaction mixture was keptat −20° C. for two days, after which O-(trimethylsilyl)hydroxylamine(26μL) was added. The mixture was slowly warmed to r.t. while stirring for3 hours and then quenched with ethyl acetate and KH₂PO₄. The aqueousphase was extracted 6 times with ethyl acetate. The combined organicextracts were concentrated in vacuo and purified by chromatography. ¹³CNMR (75 MHz, DMSO) δ 164.14, 150.60, 142.39, 133.46, 130.81, 130.09,128.58, 126.67, 126.50, 126.42, 125.60, 125.53, 125.14, 123.08, 122.94,51.06, 50.13, 38.58, 36.90, 32.94, 28.97, 24.55, 20.22.

Example 162N-(2-Morpholin-4-yl-2-oxo-ethoxy)-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1171)

General procedure I was followed using4-[2-(ammoniooxy)acetyl]morpholine chloride. ¹³C NMR (151 MHz, DMSO) δ165.43, 163.31, 151.10, 141.54, 133.44, 130.74, 129.15, 128.63, 126.99,126.67, 126.61, 125.75, 125.53, 125.26, 123.19, 122.88, 73.30, 66.00,65.86, 50.98, 50.32, 45.03, 41.42, 37.99, 36.84, 32.71, 28.64, 24.19,20.10.

Example 163N-(2-Morpholin-4-yl-2-oxo-ethoxy)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1172)

General procedure I-2 was followed using4-[2-(ammoniooxy)acetyl]morpholine chloride. ¹³C NMR (75 MHz, DMSO) δ165.46, 163.35, 150.94, 141.00, 133.40, 130.74, 129.24, 128.64, 127.08,126.77, 125.84, 125.52, 125.28, 123.14, 122.72, 73.32, 66.02, 65.89,50.09, 49.57, 45.07, 41.45, 36.60, 35.85, 32.79, 30.23, 23.87, 20.30.

Example 164N-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-methanesulfonamide(compound 1173)

General procedure I was followed using methane sulfonamide. ¹H NMR (300MHz, DMSO) δ 8.34 (d, 1H), 8.03-7.76 (m, 5H), 7.65-7.50 (m, 3H), 7.08(d, 2H), 5.30-5.17 (m, 1H), 3.16-2.96 (m, 2H), 2.90 (s, 3H), 1.92-1.68(m, 5H), 1.67-1.40 (m, 6H).

Example 1654R-Hydroxy-1-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-pyrrolidine-2S-carboxylicacid methyl ester (compound 1174)

General procedure I was followed using L-hydroxyproline methyl esterhydrochloride. ¹H NMR (600 MHz, DMSO) δ 8.35 (d, 1H), 7.93 (d, 1H), 7.78(dd, 2H), 7.56-7.47 (m, 3H), 7.39 (d, 2H), 7.11 (d, 2H), 5.07 (s, 1H),4.74 (s, 1H), 4.58-4.52 (m, 1H), 3.73 (dd, 1H), 3.66 (s, 3H), 3.29 (s,1H), 3.02 (t, 1H), 2.89 (s, 1H), 2.18 (dd, 1H), 1.98-1.91 (m, 1H),1.90-1.82 (m, 1H), 1.80-1.71 (m, 2H), 1.69-1.63 (m, 1H), 1.58-1.38 (m,6H), 1.37-1.27 (m, 1H). LC/MS (method B): RT=2.42, [M+H]⁺=501.5.

Example 1664R-Hydroxy-1-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-pyrrolidine-2S-carboxylicacid (compound 1175)

General procedure J was followed using4-hydroxy-1-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-pyrrolidine-2-carboxylicacid methyl ester (compound 1174). ¹H NMR (600 MHz, DMSO) δ 8.35 (d,1H), 7.92 (d, 1H), 7.77 (dd, 2H), 7.55-7.46 (m, 3H), 7.38 (d, 2H), 7.10(d, 2H), 5.02 (br s, 1H), 4.70 (q, 1H), 4.50-4.43 (m, 1H), 4.27-4.23 (m,1H), 3.70 (dd, 1H), 3.28 (d, 1H), 3.06-2.97 (m, 1H), 2.89-2.83 (m, 1H),2.21-2.15 (m, 1H), 1.97-1.82 (m, 2H), 1.80-1.71 (m, 2H), 1.68-1.62 (m,1H), 1.54-1.35 (m, 6H), 1.34-1.25 (m, 1H).

Example 167N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-methanesulfonamidehydrochloride (compound 1176)

General procedure I-2 was followed using methanesulfonamide. The productwas dissolved in ethyl acetate and treated with HCl in dioxane (4 M) anddiethyl ether. The precipitate was filtered to afford the titlecompound. ¹H NMR (600 MHz, DMSO) δ 9.70-8.62 (m, 1H), 8.33 (d, 1H),8.04-7.70 (m, 5H), 7.64-7.50 (m, 3H), 7.04 (s, 2H), 5.49-4.87 (m, 1H),3.14-2.98 (m, 2H), 2.86 (s, 3H), 1.94-1.85 (m, 1H), 1.82-1.47 (m, 9H),1.46-1.34 (m, 1H).

General Procedure K

To a solution of arylboronic acid (4.6 mmol) and[(1,4-hydroquinone)-rhodium(COD)]BF₄ (Son et al., J. Am. Chem. Soc.2005, 127, 12238) (2 mol %) in water/dimethoxyethane (1:1, 20 mL,degassed) was added cyclopentenone (4.6 mmol) and LiOH (8 mol %). Themixture was warmed to 50° C. and stirred overnight. Additional water wasadded, and the mixture was extracted with dichloromethane. The organicphase was separated, dried and concentrated in vacuo to a brown oil.This crude intermediate was redissolved in 40 mL dichloroethane. Afterthe addition of (+)-(R)-1-naphthalen-1-yl-ethylamine (4.6 mmol) andNaBH(OAc)₃ (1.7 eq.), the reaction mixture was stirred overnight at r.t.The mixture was diluted with dichloromethane, washed with aqueousNaHCO₃, water and brine. The organic phase was dried, concentrated invacuo, and purified on silica gel to a colorless oil. Diastereoisomerswere separated by chiral HPLC.

Example 168{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid ethyl ester (compound 1177/1178/1179/1180)

General procedure K was followed using4-(2-ethoxy-2-oxoethoxy)-phenylboronic acid. The four resultingdiastereoisomers were separated using preparative chiral HPLC on aChiralpak AD-H column 250×20 mm, 5 μm at 25° C., UV detection at 280 nm.Isocratic separation with n-heptan:ethanol:NEt₃:CH₃COOH (75:25:0.1:0.1);flow rate=7.0 mL/min. Compound 1177: RT=11.05. ¹³C NMR (151 MHz, DMSO) δ168.78, 155.62, 141.94, 138.53, 133.42, 130.87, 128.59, 127.74, 126.50,125.67, 125.56, 125.18, 123.01, 122.91, 114.14, 64.60, 60.47, 56.58,51.18, 42.82, 42.06, 32.52, 32.14, 24.24, 13.96. Compound 1178:RT=12.77. ¹³C NMR (151 MHz, DMSO) δ 168.77, 155.55, 142.09, 138.62,133.39, 130.95, 128.58, 127.70, 126.49, 125.65, 125.57, 125.17, 122.95,122.93, 114.14, 64.59, 60.46, 55.97, 51.02, 42.08, 40.44, 33.65, 33.23,24.15, 13.95. Compound 1179: RT=18.35. ¹³C NMR (151 MHz, DMSO) δ 168.75,155.54, 142.03, 138.60, 133.39, 130.83, 128.59, 127.63, 126.54, 125.67,125.54, 125.19, 123.01, 122.89, 114.14, 64.57, 60.45, 56.16, 50.81,42.00, 41.33, 33.30, 32.93, 24.05, 13.93. Compound 1180: RT=23.96. ¹³CNMR (151 MHz, DMSO) δ 168.91, 155.77, 141.97, 138.42, 133.53, 130.96,128.75, 127.82, 126.80, 125.87, 125.69, 125.37, 123.20, 123.01, 114.28,64.72, 60.60, 56.62, 51.37, 42.66, 42.05, 32.30, 31.84, 24.09, 14.09.

Example 1693-{4-[(3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid methyl ester (compounds 1181/1182/1183/1184)

General procedure K was followed using4-(2-methoxycarbonylethyl)-phenylboronic acid. The four resultingdiastereomers were separated by preparative chiral HPLC on a ChiralpakAD-H column 250×20 mm, 5 μm at 25° C., UV detection at 280 nm. Isocraticseparation with n-heptane:2-propanol:NEt₃:CH₃COOH (75:25:0.1:0.1); flowrate=7.0 mL/min. Compound 1181: RT=7.74. ¹³C NMR (126 MHz, DMSO) δ172.59, 143.57, 142.01, 137.65, 133.41, 130.87, 128.57, 127.92, 126.80,126.47, 125.63, 125.54, 125.15, 122.99, 122.90, 56.66, 51.21, 51.15,43.23, 41.97, 34.84, 32.59, 31.99, 29.73, 24.23. Compound 1182: RT=8.75.¹³C NMR (126 MHz, DMSO) δ 172.59, 143.70, 142.08, 137.57, 133.40,130.95, 128.56, 127.92, 126.77, 126.47, 125.62, 125.55, 125.15, 122.95,122.93, 56.07, 51.14, 51.07, 42.50, 40.37, 34.82, 33.68, 33.06, 29.71,24.13. Compound 1183: RT=11.47. ¹³C NMR (126 MHz, DMSO) δ 172.58,143.74, 142.15, 137.56, 133.40, 130.86, 128.58, 127.92, 126.71, 126.47,125.62, 125.53, 125.15, 122.99, 122.92, 56.30, 51.14, 50.92, 42.42,41.31, 34.79, 33.14, 33.06, 29.69, 24.14. Compound 1184: RT=15.95. ¹³CNMR (126 MHz, DMSO) δ 172.60, 143.44, 141.96, 137.66, 133.40, 130.88,128.58, 127.92, 126.76, 126.50, 125.63, 125.54, 125.15, 122.99, 122.91,56.63, 51.34, 51.15, 42.96, 42.24, 34.81, 32.06, 31.86, 29.72, 24.12.

Example 170{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid (compound 1185)

General procedure J was followed using{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid ethyl ester (compound 1178). ¹³C NMR (75 MHz, DMSO) δ 171.24,156.64, 137.18, 136.14, 133.30, 130.49, 128.74, 127.83, 127.45, 126.43,125.68, 125.53, 123.96, 122.44, 113.96, 66.07, 55.36, 50.31, 42.31,37.78, 33.41, 31.62, 21.55.

Example 171{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid (compound 1186)

General procedure J was followed using{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid ethyl ester (compound 1180). ¹³C NMR (151 MHz, DMSO) δ 170.60,156.80, 141.57, 136.68, 133.37, 130.84, 128.59, 127.26, 126.57, 125.70,125.55, 125.19, 123.06, 122.85, 114.01, 67.44, 56.46, 51.22, 42.56,42.24, 32.23, 31.56, 23.97.

Example 172{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid (compound 1187)

General procedure J was followed using{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid ethyl ester (compound 1177). ¹³C NMR (75 MHz, DMSO) δ 171.08,156.66, 136.78, 136.00, 133.35, 130.36, 128.78, 127.89, 127.48, 126.50,125.73, 125.53, 123.89, 122.37, 114.06, 65.94, 55.64, 50.45, 42.84,32.02, 29.87, 21.92 (one aliphatic signal not visible).

Example 173{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid (compound 1188)

General procedure J was followed using{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid ethyl ester (compound 1179). ¹³C NMR (151 MHz, DMSO) δ 170.47,156.25, 136.56, 133.51, 130.39, 129.03, 128.77, 127.82, 126.95, 126.18,125.69, 124.37, 122.57, 114.29, 64.79, 55.73, 50.52, 42.20, 37.68,33.44, 30.61, 21.02 (one aromatic signal not visible).

Example 174 3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)cyclopentyl]-phenyl}-propionic acid (compound 1189)

General procedure J was followed using3-{4-[(3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid methyl ester (compound 1181). ¹³C NMR (151 MHz, DMSO) δ 173.70,142.32, 138.38, 133.37, 130.49, 128.73, 128.01, 127.68, 126.75, 126.32,125.64, 125.54, 123.72, 122.60, 56.03, 50.85, 43.18, 35.25, 31.87,30.49, 29.85, 22.43 (two signals not visible).

Example 1753-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid hydrochloride (compound 1190)

General procedure J was followed using3-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid methyl ester (compound 1183). ¹³C NMR (151 MHz, DMSO) δ 173.64,141.55, 138.53, 133.88, 133.34, 130.17, 128.91, 128.88, 128.10, 126.96,126.73, 126.11, 125.53, 124.62, 122.36, 55.50, 50.35, 42.42, 36.83,35.13, 33.11, 30.01, 29.78, 20.48.

Example 1763-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid (compound 1191)

General procedure J was followed using3-{4[(3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid methyl ester (compound 1182). ¹³C NMR (75 MHz, DMSO) δ 173.69,143.29, 141.05, 138.04, 133.38, 130.84, 128.60, 127.94, 126.78, 126.71,125.78, 125.54, 125.27, 123.14, 122.85, 56.00, 50.99, 42.49, 39.89,35.25, 33.25, 33.06, 29.84, 23.58.

Example 1773-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid (compound 1192)

General procedure J was followed using3-{4-[(3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid methyl ester (compound 1184). ¹³C NMR (151 MHz, DMSO) δ 173.72,142.67, 139.63, 138.24, 133.36, 130.64, 128.67, 127.99, 127.19, 126.69,126.03, 125.53, 125.45, 123.40, 122.74, 56.27, 51.09, 42.92, 40.90,35.24, 31.90, 30.70, 29.85, 22.88.

Example 178{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid ethyl ester (compounds 1193/1194/1195/1196)

General procedure K was followed using3-(2-ethoxy-2-oxoethoxy)-phenylboronic acid. Mixture of fourdiastereomers: ¹+1 NMR (300 MHz, DMSO) δ 8.29 (d, 1H), 7.91 (dd, 1H),7.75 (dd, 2H), 7.58-7.42 (m, 3H), 7.21-7.08 (m, 1H), 6.88-6.62 (m, 3H),4.74-4.68 (m, 2H), 4.70-4.58 (m, 1H), 4.21-4.08 (m, 2H), 3.40-2.74 (m,2H), 2.34-1.30 (m, 9H), 1.26-1.13 (m, 3H). The four diastereoisomerswere separated using preparative chiral HPLC on a Chiralpak AD-H column250×20 mm, 5 μm at 25° C., UV detection at 280 nm. Isocratic separationwith 2-propanol:heptan: NEt₃:CH₃COOH (90:10:0.1:0.1); flow rate=17.0mL/min. Diastereomer 1 (compound 1193): RT=21.65. Diastereomer 2(compound 1194): RT=24.65. Diastereomer 3 (compound 1195): RT=45.89.Diastereomer 4 (compound 1196): RT=52.85.

Example 1793-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid ethyl ester (compounds 1197/1198/1198/1200)

General procedure K was followed using3-(2-ethoxycarbonylethyl)-phenyl-boronic acid. Mixture of 4diastereomers: ¹H NMR (300 MHz, DMSO) δ 8.34-8.24 (m, 1H), 7.96-7.86 (m,1H), 7.75 (dd, 2H), 7.58-7.43 (m, 3H), 7.20-6.92 (m, 4H), 4.71-4.59 (m,1H), 4.08-3.95 (m, 2H), 3.36-2.93 (m, 2H), 2.87-2.71 (m, 2H), 2.63-2.51(m, 2H), 2.32-1.32 (m, 9H), 1.20-1.07 (m, 3H). The four diastereomerswere separated by preparative chiral HPLC on a Chiralpak AD-H column250×20 mm, 5 μm at 25° C., UV detection at 280 nm. Isocratic separationwith n-heptane:ethanol:NEt₃:CH₃COOH (80:20:0.1:0.1); flow rate=17.0mL/min. Diastereomer 1 (compound 1197): RT=7.38. Diastereomer 2(compound 1198): RT=9.09. Diastereomer 3 (compound 1199): RT=10.01.Diastereomer 4 (compound 1200): RT=14.56.

Example 180{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid hydrochloride (compound 1201)

General procedure j was followed using{3-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acidethyl ester (compound 1196). ¹+1 NMR (300 MHz, DMSO) δ 10.25-9.81 (m,1H), 9.55-9.21 (m, 1H), 8.30 (d, 1H), 8.10-7.95 (m, 3H), 7.68-7.54 (m,3H), 7.15 (t, 1H), 6.78-6.65 (m, 3H), 5.39-5.27 (m, 1H), 4.60 (s, 2H),3.74-3.63 (m, 1H), 3.59-3.42 (m, 1H), 2.52-2.34 (m, 1H), 2.23-2.12 (m,1H), 2.10-1.98 (m, 1H), 1.90-1.68 (m, 5H), 1.59-1.42 (m, 1H).

Example 181{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid (compound 1202)

General procedure j was followed using{3-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acidethyl ester (compound 1193). ¹H NMR (300 MHz, DMSO) δ 8.27 (d, 1H), 7.95(d, 1H), 7.84 (t, 2H), 7.61-7.47 (m, 3H), 7.09 (t, 1H), 6.70-6.59 (m,3H), 4.93 (q, 1H), 4.42 (s, 2H), 3.32-3.08 (m, 2H), 2.05-1.61 (m, 5H),1.56-1.30 (m, 4H).

Example 182{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid (compound 1203)

General procedure j was followed using{3-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acidethyl ester (compound 1194). ¹H NMR (300 MHz, DMSO) δ 8.26 (d, 1H),7.98-7.91 (m, 1H), 7.83 (t, 2H), 7.60-7.47 (m, 3H), 7.10 (t, 1H),6.79-6.70 (m, 2H), 6.69-6.61 (m, 1H), 4.92 (q, 1H), 4.42 (s, 2H),3.20-3.06 (m, 1H), 2.86-2.71 (m, 1H), 2.23-2.09 (m, 1H), 1.90-1.43 (m,8H).

Example 1843-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid hydrochloride (compound 1204)

General procedure J was followed using{3-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acidethyl ester (compound 1195). ¹H NMR (300 MHz, DMSO) δ 10.14 (br s, 1H),9.51 (br s, 1H), 8.30 (d, 1H), 8.09-7.95 (m, 3H), 7.70-7.53 (m, 3H),7.20 (t, 1H), 6.91-6.80 (m, 2H), 6.77-6.68 (m, 1H), 5.40-5.23 (m, 1H),4.64 (s, 2H), 3.61-3.39 (m, 1H), 2.96-2.76 (m, 1H), 2.23-1.78 (m, 6H),1.72 (d, 3H).

Example 1833-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid (compound 1205)

General procedure J was followed using3-{3-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid ethyl ester (compound 1199). ¹H NMR (300 MHz, DMSO) δ 8.40-8.23 (m,1H), 7.99-7.86 (m, 1H), 7.85-7.67 (m, 2H), 7.61-7.41 (m, 3H), 7.21-6.85(m, 4H), 4.76-4.57 (m, 1H), 3.28-3.06 (m, 2H), 2.85-2.65 (m, 2H),2.13-1.29 (m, 9H).

Example 1853-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid (compound 1206)

General procedure J was followed using3-{3-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid ethyl ester (compound 1197). ¹H NMR (300 MHz, DMSO) δ 8.29 (d, 1H),7.96-7.87 (m, 1H), 7.76 (dd, 2H), 7.56-7.43 (m, 3H), 7.20-6.95 (m, 4H),4.67 (q, 1H), 3.08-2.94 (m, 1H), 2.78 (t, 3H), 2.54-2.45 (m, 2H),2.22-2.08 (m, 1H), 1.92-1.31 (m, 8H).

Example 1863-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid (compound 1207)

General procedure J was followed using3-{3-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid ethyl ester (compound 1198). ¹H NMR (300 MHz, DMSO) δ 8.29 (d, 1H),7.92 (dd, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.57-7.43 (m, 3H), 7.17-7.07(m, 1H), 7.04-6.92 (m, 3H), 4.69 (q, 1H), 3.27-3.07 (m, 2H), 2.74 (t,2H), 2.50-2.41 (m, 2H), 2.08-1.84 (m, 3H), 1.64-1.28 (m, 6H).

Example 1873-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid hydrochloride (compound 1208)

General procedure J was followed using3-{3-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid ethyl ester (compound 1200). The product was dissolved in ethylacetate and treated with HCl in dioxane (4 M) and diethyl ether. Theprecipitate was filtered to afford the title compound. ¹H NMR (300 MHz,DMSO) δ 12.11 (br s, 1H), 10.15 (br s, 1H), 9.46 (br s, 1H), 8.30 (d,1H), 8.10-7.96 (m, 3H), 7.69-7.56 (m, 3H), 7.20 (t, 1H), 7.10-7.01 (m,3H), 5.32 (s, 1H), 3.69 (dd, 1H), 3.55-3.41 (m, 2H), 3.00-2.85 (m, 1H),2.78 (t, 2H), 2.50 (dd, 1H), 2.23-1.68 (m, 8H).

Preparation 5: 3-(4-Iodophenyl)-cyclohexan-1-one

To a solution of 1,4-diiodobenzene (1.0 g, 3.0 mmol) in 6 mL dry THF wasadded isopropyl magnesium chloride (2 M in THF) at −30° C. The reactionmixture was stirred for 1 hour at −20° C. Meanwhile, LiCl (26 mg, 0.61mmol), CuI (58 mg, 0.30 mmol) and TMSCl (329 mg, 3.0 mmol) were added toa solution of 2-cyclohexen-1-one (291 mg, 3.0 mmol) in dry THF (3 mL),and the resulting solution was added to the Grignard solution. Thereaction mixture was stirred another hour at −20° C., then slowly warmedto r.t. over the course of an hour and finally quenched with saturatedNH₄Cl (aq) and extracted with diethyl ether. The organic phase was dried(Na₂SO₄), filtered and concentrated under reduced pressure. The residuewas purified by chromatography on silica gel (PE-EtOAc 100:0 to 80:20)to afford the title compound.

Example 188[3-(4-Iodo-phenyl)-cyclohexyl]-(1-naphthalen-1-yl-ethyl)-amine (compound1209)

To a solution of 3-(4-iodophenyl)-cyclohexan-1-one (preparation 5) (5.0g, 16.7 mmol) in 15 mL dry DCE were added AcOH (1.20 g, 20 mmol),NaBH(OAc)₃ (4.96 g, 23.4 mmol), and (+)-(R)-1-naphthalen-1-yl-ethylamine(2.85 g, 16.7 mmol), and the mixture was stirred overnight at r.t. Afterthe addition of NaHCO₃, the mixture was extracted with ethyl acetate.The organic phase was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by chromatography on silicagel (PE-EtOAc 100:0 to 75:25) to afford two fractions, each consistingof predominantly one diastereomer. The less polar fraction was the titlecompound. ¹³C NMR (75 MHz, DMSO) δ 147.07, 142.36, 136.65, 133.43,130.79, 129.09, 128.56, 126.39, 125.56, 125.49, 125.10, 123.03, 122.91,90.81, 51.00, 50.04, 38.58, 36.51, 32.97, 28.90, 24.52, 20.18.

Example 1891-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-pyrrolidin-2-one(compound 1210)

3-(4-Iodophenyl)-cyclohexan-1-one (compound 1209) (150 mg, 0.33 mmol),2-pyrrolidone (0.40 mmol), glycine (5 mg, 0.07 mmol), K₃PO₄ (176 mg,0.83 mmol) and CuI (3 mg, 0.017 mmol) were suspended in 3 mL dry dioxaneand heated in a microwave oven at 130° C. for 8 hours. The mixture wasextracted with ethyl acetate, and the organic phase was dried overMgSO₄, filtered and concentrated under reduced pressure. The residualoil was purified by chromatography to afford the title compound as asolid. ¹³C NMR (75 MHz, DMSO) δ 173.34, 142.88, 142.38, 137.15, 133.45,130.83, 128.58, 126.59, 126.39, 125.59, 125.53, 125.12, 123.05, 122.92,119.25, 50.87, 50.04, 47.97, 38.82, 36.38, 33.38, 32.12, 28.95, 24.53,20.28, 17.33.

Example 1903-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-oxazolidin-2-one(compound 1211)

3-(4-Iodophenyl)-cyclohexan-1-one (compound 1209) (150 mg, 0.33 mmol),2-oxazolidinone (0.40 mmol, 1.2 eq.), glycine (5 mg, 0.07 mmol), K₃PO₄(176 mg, 0.83 mmol) and CuI (3 mg, 0.017 mmol) were suspended in 3 mLdry dioxane under argon and heated at 120° C. for 35 hours. The mixturewas extracted with ethyl acetate, and the organic phase was dried overMgSO₄, filtered and concentrated under reduced pressure. The residualoil was purified by chromatography to afford the title compound as anoil. ¹³C NMR (75 MHz, DMSO) δ 154.80, 142.50, 142.34, 136.04, 133.44,130.82, 128.56, 126.83, 126.38, 125.56, 125.50, 125.09, 123.02, 122.90,117.87, 61.26, 50.88, 50.03, 44.67, 38.80, 36.28, 33.37, 28.93, 24.49,20.26.

Example 191N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-acetamide(compound 1212)

3-(4-Iodophenyl)-cyclohexan-1-one (compound 1209) (150 mg, 0.33 mmol),acetamide (0.40 mmol, 1.2 eq.), glycine (5 mg, 0.07 mmol), K₃PO₄ (176mg, 0.83 mmol) and CuI (3 mg, 0.017 mmol) were suspended in 3 mL drydioxane under argon and heated at 120° C. for 35 hours. The mixture wasextracted with ethyl acetate, and the organic phase was dried overMgSO₄, filtered and concentrated under reduced pressure. The residualoil was purified by chromatography to afford the title compound as anoil. ¹³C NMR (75 MHz, DMSO) δ 167.85, 142.41, 141.95, 136.86, 133.49,130.87, 128.60, 126.61, 126.42, 125.60, 125.55, 125.13, 123.08, 122.95,118.87, 50.95, 50.11, 38.92, 36.40, 33.44, 29.02, 24.55, 23.82, 20.35.

Example 1924-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-tetrahydro-pyran-4-ol(compound 1213)

To a solution of 3-(4-iodophenyl)-cyclohexan-1-one (compound 1209) (455mg, 1 mmol) in dry THF (5 mL) was added isopropyl magnesium chloride (1mL of a 2M solution in THF) at 40° C., and the resulting mixture wasstirred at −10° C. for 4 hours. A solution of tetrahydro-4H-pyran-4-one(150 mg, 1.5 mmol) in 0.5 mL dry THF was added, and the reaction wasstirred for another hour at 0° C. and at r.t. overnight. After quenchingwith NH₄Cl, the mixture was extracted with ethyl acetate, which wasdried (Na₂SO₄), filtered and concentrated under reduced pressure.Chromatography (EtOAc) afforded the title compound as an oil. ¹³C NMR(75 MHz, DMSO) δ 146.84, 145.25, 142.40, 133.46, 130.83, 128.58, 126.40,126.07, 125.59, 125.54, 125.13, 124.42, 123.04, 122.93, 68.67, 63.07,50.87, 50.06, 38.89, 38.31, 36.53, 33.30, 29.02, 24.50, 20.31.

Example 193[3-(4-Imidazol-1-yl-phenyl)-cyclohexyl]-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1214)

3-(4-Iodophenyl)-cyclohexan-1-one (compound 1209) (150 mg, 0.33 mmol),imidazole (0.40 mmol, 1.2 eq.), glycine (5 mg, 0.07 mmol), K₃PO₄ (176mg, 0.83 mmol) and CuI (3 mg, 0.017 mmol) were suspended in 3 mL drydioxane under argon and heated at 120° C. for 35 hours. The mixture wasextracted with ethyl acetate, and the organic phase was dried overMgSO₄, filtered and concentrated under reduced pressure. The residualoil was purified by chromatography to afford the title compound as anoil. ¹³C NMR (75 MHz, DMSO) δ 146.12, 142.37, 135.32, 134.58, 133.44,130.82, 129.55, 128.58, 127.83, 126.41, 125.59, 125.52, 125.12, 123.02,122.91, 120.17, 117.92, 50.91, 50.03, 38.68, 36.49, 33.23, 28.89, 24.52,20.23.

Example 1941-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-cyclopentanol(compound 1215)

To a solution of 3-(4-iodophenyl)-cyclohexan-1-one (compound 1209) (125mg, 0.27 mmol) in dry THF (4 mL) was added isopropyl magnesium chloride(0.27 mL of a 2M solution in THF) at −20° C., and the mixture wasstirred at −20° C. for 2 hours, after which cyclopentanone (34 mg, 0.41mmol) in 0.2 mL THF was added. The mixture was stirred at the sametemperature for another 30 min, then slowly warmed to r.t. overnight.After quenching with aqueous NH₄Cl, the mixture was extracted with ethylacetate, and the organic phases were dried, filtered and concentratedunder reduced pressure. Chromatography (EtOAc-PE) afforded the titlecompound as an oil. ¹³C NMR (75 MHz, DMSO) δ 145.51, 144.83, 142.35,133.44, 130.82, 128.57, 126.39, 125.81, 125.57, 125.51, 125.10, 124.86,123.02, 122.90, 81.17, 50.85, 50.05, 41.48, 41.45, 38.88, 36.53, 33.36,29.01, 24.48, 23.51, 20.30.

Example 1941-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-ethanone(compound 1216)

To a solution of 3-(4-iodophenyl)-cyclohexan-1-one (compound 1209) (200mg, 0.44 mmol) in dry THF (5 mL) was added isopropylmagnesium chloride(2 M in THF) at −30° C. After stirring for 45 min at −30→−15° C., asolution of N-methoxy-N-methylacetamide (49 mg, 0.48 mmol) in THF (2 mL)was added. The reaction mixture was stirred another 30 min at −20→−15°C. and then warmed to 0° C. over the course of 15 min. The reaction wasquenched with NH₄Cl (aq.) and extracted with ethyl acetate. The organicphase was dried over Na₂SO₄, filtered and concentrated under reducedpressure. Chromatography (PE-EtOAc 100:0 to 50:50) afforded the titlecompound. ¹³C NMR (75 MHz, DMSO) δ 197.29, 152.96, 142.37, 134.49,133.45, 130.80, 128.58, 128.09, 126.82, 126.43, 125.60, 125.52, 125.14,123.08, 122.93, 51.06, 50.11, 38.38, 37.09, 32.81, 28.92, 26.46, 24.52,20.16.

Example 1954-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-tetrahydro-pyran-4-olhydrochloride (compound 1217)

4-{4-[3-(1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-tetrahydro-pyran-4-ol(compound 1213) was dissolved in ethyl acetate and treated with HCl indioxane (4 M) and diethyl ether. The precipitate was filtered to affordthe title compound. ¹³C NMR (75 MHz, DMSO) δ 147.31, 142.53, 133.86,133.35, 130.24, 128.93, 128.87, 127.00, 126.09, 125.50, 124.67, 122.31,68.72, 63.05, 51.97, 50.25, 38.29, 35.33, 33.63, 31.08, 26.00, 20.73,19.34.

Example 196{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanol(compound 1218)

To a solution of4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid(compound 1056) (0.50 g, 1.34 mmol) in dry THF (5 mL) was addedborane-THF complex (1M in THF, 5.35 mmol) at −78° C. The reactionmixture was slowly heated to 0° C. in the course of 1.5 hours and thenstands at r.t. overnight. After cooling in an icebath, the mixture wasquenched with water, diluted with aqueous NaHCO₃ and extracted withdiethyl ether. Combined organic extracts were dried over MgSO₄ andconcentrated under reduced pressure. Chromatography (EtOAc-PE 1:1)afforded the title compound as an oil. ¹³C NMR (75 MHz, MeOH) δ 147.33,142.64, 139.93, 135.58, 132.69, 130.06, 128.25, 128.10, 127.88, 126.94,126.66, 126.42, 124.36, 123.81, 65.12, 52.01, 51.93, 39.65, 38.69,34.52, 30.84, 24.26, 21.78.

Example 1971-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-cyclobutanol(compound 1219)

To a solution of 3-(4-iodophenyl)-cyclohexan-1-one (compound 1209) (250mg, 0.55 mmol) in dry THF (1 mL) under argon at −78° C. was added n-BuLi(0.37 mL, 1.6 M in THF). The resulting red solution was stirred for 2min at the same temperature, and then cyclobutanone (45 μL, 0.60 mmol)was added dropwise. The now light yellow solution was stirred at −78° C.for 10 min before quenching with 1.2 M KH₂PO₄ (aq.). The mixture wasextracted with ethyl acetate, and the organic phases were dried andconcentrated in vacuo. Chromatography (EtOAc-PE 1:1) afforded the titlecompound. ¹³C NMR (75 MHz, DMSO) δ 145.25, 144.81, 142.39, 133.44,130.82, 128.57, 126.39, 126.03, 125.59, 125.53, 125.12, 124.60, 123.04,122.92, 74.88, 50.86, 50.05, 38.88, 37.05, 36.58, 33.33, 29.01, 24.51,20.30, 12.59.

Example 1982-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-malonicacid diethyl ester (compound 1220)

3-(4-Iodophenyl)-cyclohexan-1-one (compound 1209) (0.80 g, 1.76 mmol),malonic acid diethyl ester (0.56 g, 3.52 mmol), CsCO₃ (0.86 g, 2.64mmol), CuI (33 mg, 0.18 mmol) and 2-hydroxybiphenyl (60 mg, 0.35 mmol)were mixed in dry THF (5 mL) under argon and heated at 100° C. for 8days. The mixture was diluted with water and extracted with ethylacetate. The organic phase was washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. Chromatography(PE-EtOAc 100:0 to 50:50) afforded the title compound as a solid, whichwas recrystallized in ethanol. ¹³C NMR (75 MHz, DMSO) δ 167.91, 147.02,142.35, 133.44, 130.82, 130.05, 128.88, 128.55, 126.56, 126.39, 125.58,125.51, 125.11, 123.02, 122.92, 61.10, 56.27, 50.92, 50.02, 38.78,36.63, 33.11, 28.91, 24.48, 20.25, 13.74.

Example 199{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-acetic acidethyl ester (compound 1221)

To a solution of2-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-malonic aciddiethyl ester (compound 1220) (100 mg, 0.20 mmol) in DMSO (5 mL) wasadded water (3.6 mg, 0.20 mmol) and LiCl (17 mg, 0.41 mmol). Theresulting mixture was heated at 150° C. overnight, diluted with waterand extracted with EtOAc. The organic phase was washed with brine, driedover Na₂SO₄ and concentrated under reduced pressure. Chromatography(PE-EtOAc 50:50) afforded the title compound as an oil. ¹³C NMR (75 MHz,DMSO) δ 171.14, 145.78, 142.40, 133.45, 131.40, 130.83, 128.89, 128.57,126.53, 126.39, 125.59, 125.53, 125.12, 123.05, 122.93, 60.06, 50.91,50.05, 39.81, 38.89, 36.59, 33.27, 28.96, 24.52, 20.29, 13.98.

Example 200{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-acetic acid(compound 1222)

A solution of{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-acetic acidethyl ester (compound 1221) (400 mg) in methanol (5 mL) was treated with2M NaOH in methanol and stirred for 1 day at r.t. Methanol was removedunder reduced pressure. The remaining aqueous phase was acidified with4M aqueous HCl and extracted with ethyl acetate. The organic phase wasdried over Na₂SO₄, filtered, and concentrated under reduced pressure.Chromatography (MeOH CH₂Cl₂ 20:80) afforded the title compound as asolid. ¹³C NMR (75 MHz, DMSO) δ 172.72, 144.65, 133.42, 132.24, 130.63,129.05, 128.70, 127.24, 126.41, 126.07, 125.52, 125.45, 123.63, 122.71,50.69, 40.27, 37.09, 36.18, 32.57, 27.93, 23.24, 19.97.

Example 2013-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-oxetan-3-ol(compound 1223)

To a solution of 3-(4-iodophenyl)-cyclohexan-1-one (compound 1209) (3.7g, 8.1 mmol) in dry THF (25 mL) under argon was added isopropylmagnesium chloride (8.1 mL of a 2M solution in THF) at −30-−40° C. Thereaction mixture was heated to −10-0° C. and stirred at this temperaturefor 5 hours, upon which a solution of 3-oxetanone (0.50 g, 6.9 mmol) inTHF (3 mL) was added. Stirring was continued for another 2 hours at thesame temperature. The reaction mixture was finally heated slowly to r.t.overnight, quenched with NH₄Cl and extracted with ethyl acetate. Theorganic phase was washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. Chromatography (CHCl₃-MeOH 100:0 to95:5) afforded the title compound as an oil. ¹³C NMR (75 MHz, DMSO) δ146.09, 142.40, 141.30, 133.47, 130.83, 128.59, 126.41, 126.34, 125.59,125.54, 125.13, 124.31, 123.07, 122.94, 85.13, 73.78, 50.96, 50.13,38.89, 36.62, 33.27, 29.03, 24.53, 20.31.

Example 202{3-[4-(3-Fluoro-oxetan-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1224)

To a solution of3-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-oxetan-3-olin CH₂Cl₂ (compound 1223) (5 mL) was added diethylaminosulfurtrifluoride (0.21 mL). The mixture was stirred for ½ hour, quenched withNaHCO₃ and extracted with CH₂Cl₂. The organic phase was dried overNa₂SO₄, filtered and concentrated under reduced pressure. Chromatography(MeOH—CH₂Cl₂ 1:99) afforded the title compound as an oil. ¹³C NMR (75MHz, DMSO) δ 148.01, 142.39, 134.93, 134.62, 133.47, 130.83, 128.59,126.88, 126.42, 125.61, 125.54, 125.14, 124.45, 124.35, 123.07, 122.94,97.01, 94.31, 81.42, 81.08, 50.98, 50.09, 38.71, 36.73, 33.11, 28.97,24.53, 20.25.

Example 203{3-[4-(3-Amino-3-methyl-but-1-ynyl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1225)

To a solution of 3-(4-iodophenyl)-cyclohexan-1-one (compound 1209) (150mg, 0.33 mmol) in diethylamine (3 mL, degassed by bubbling argon throughthe solution for 5 min) were added PdCl₂(Ph₃P)₂ (15 mg) and CuI (8 mg).The mixture was argon degassed for another 5 min., cooled to 0° C., and2-methyl-3-butin-2-yl-amin (137 mg, 1.65 mmol) was added. The reactionmixture was stirred at 0° C. for 30 min and at r.t. for 1 hour andextracted with EtOAc. The organic phase was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. Chromatography (EtOAc) afforded thetitle compound as an oil. ¹³C NMR (126 MHz, CDCl3) δ 146.47, 141.93,133.09, 130.37, 130.17, 127.84, 125.90, 125.82, 124.69, 124.31, 122.61,122.41, 119.69, 78.93, 51.09, 49.97, 44.76, 39.10, 37.90, 36.30, 32.16,31.32, 29.36, 23.45, 19.73.

General Procedure L

Acid chloride (41 μmol),N-hydroxy-4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamidine(compound 1051, 49 μmol) and CDI (45 μmol) in 150 μl. DMF were shaken atr.t. overnight. Additional CDI (45 μmol) in 50 μL DMF were added, andthe reaction mixture was heated at 115° C. overnight. The product waspurified by preparative HPLC.

Example 204{3-[4-(5-Cyclopropyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1226)

General procedure L was followed using cyclopropanecarbonyl chloride. ¹HNMR (600 MHz, DMSO) δ 8.35 (d, 1H), 7.93 (d, 1H), 7.83-7.74 (m, 4H),7.56-7.47 (m, 3H), 7.18 (d, 2H), 4.74 (s, 1H), 3.08-3.00 (m, 1H),2.93-2.86 (m, 1H), 2.41-2.35 (m, 1H), 1.93-1.82 (m, 1H), 1.81-1.72 (m,2H), 1.70-1.63 (m, 1H), 1.56-1.39 (m, 6H), 1.36-1.24 (m, 3H), 1.20-1.14(m, 2H).

Example 205{3-[4-(5-Cyclopentyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1227)

General procedure L was followed using cyclopentanecarbonyl chloride. ¹HNMR (600 MHz, DMSO) δ 8.36 (d, 1H), 7.93 (d, 1H), 7.82 (d, 2H), 7.80 (d,1H), 7.76 (d, 1H), 7.55-7.48 (m, 3H), 7.20 (d, 2H), 4.74 (s, 1H), 3.47(dt, 1H), 3.08-3.01 (m, 1H), 2.92-2.87 (m, 1H), 2.16-2.09 (m, 2H),1.92-1.83 (m, 3H), 1.81-1.72 (m, 4H), 1.72-1.63 (m, 3H), 1.56-1.40 (m,6H), 1.37-1.28 (m, 1H).

Example 206{3-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1228)

General procedure L was followed using acetyl chloride. ¹H NMR (600 MHz,DMSO) δ 8.36 (d, 1H), 7.93 (d, 1H), 7.82 (d, 2H), 7.79 (d, 1H), 7.76 (d,1H), 7.56-7.47 (m, 3H), 7.19 (d, 2H), 4.71 (s, 1H), 3.08-3.00 (m, 1H),2.91-2.84 (m, 1H), 2.64 (s, 3H), 1.93-1.83 (m, 1H), 1.81-1.61 (m, 3H),1.56-1.37 (m, 6H), 1.35-1.27 (m, 1H).

Example 207{3-[4-(5-Isopropyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1229)

General procedure L was followed using isobuturyl chloride. ¹H NMR (600MHz, DMSO) δ 8.36 (d, 1H), 7.93 (d, 1H), 7.83 (d, 2H), 7.77 (d, 1H),7.76 (d, 1H), 7.56-7.47 (m, 3H), 7.19 (d, 2H), 4.74-4.66 (m, 1H), 3.34(m, 1H overlaying water signal), 3.08-3.01 (m, 1H), 2.91-2.86 (m, 1H),1.93-1.83 (m, 1H), 1.82-1.73 (m, 2H), 1.70-1.64 (m, 1H), 1.44 (d, 3H),1.55-1.26 (m, 4H), 1.37 (d, 6H).

Example 208{3-[4-(5-tert-Butyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-(R)-1-naphthalen-1-yl-ethyl)-amine(compound 1230)

General procedure L was followed using 2,2-dimethyl-propionyl chloride.¹H NMR (600 MHz, DMSO) δ 8.36 (d, 1H), 7.93 (d, 1H), 7.83 (d, 2H), 7.79(d, 1H), 7.76 (d, 1H), 7.56-7.47 (m, 3H), 7.20 (d, 2H), 4.70 (s, 1H),3.08-3.01 (m, 1H), 2.91-2.85 (m, 1H), 1.94-1.83 (m, 1H), 1.81-1.73 (m,2H), 1.70-1.63 (m, 1H), 1.57-1.38 (m, 6H), 1.44 (s, 9H), 1.36-1.26 (m,1H).

Example 209{3-[4-(5-Cyclohexyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)amine (compound 1231)

General procedure L was followed using cyclohexanecarbonyl chloride. ¹HNMR (600 MHz, DMSO) δ 8.36 (d, 1H), 7.93 (d, 1H), 7.82 (d, 2H), 7.79 (d,1H), 7.76 (d, 1H), 7.56-7.47 (m, 3H), 7.19 (d, 2H), 4.72 (q, 1H),3.13-3.01 (m, 2H), 2.91-2.86 (m, 1H), 2.10-2.02 (m, 2H), 1.93-1.83 (m,1H), 1.81-1.72 (m, 4H), 1.70-1.56 (m, 4H), 1.55-1.36 (m, 8H), 1.35-1.23(m, 2H).

Example 210(3-{4-[5-(3-Methyl-butyl)-[1,2,4]oxadiazol-3-yl]-phenyl}-cyclohexyl)-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1232)

General procedure L was followed using 4-methyl-pentanoyl chloride. ¹HNMR (600 MHz, DMSO) δ 8.36 (d, 1H), 7.93 (d, 1H), 7.83 (d, 2H), 7.80 (d,1H), 7.77 (d, 1H), 7.56-7.48 (m, 3H), 7.20 (d, 2H), 4.77-4.71 (m, 1H),3.08-3.01 (m, 1H), 3.00-2.96 (m, 2H), 2.92-2.88 (m, 1H), 1.92-1.83 (m,1H), 1.82-1.73 (m, 2H), 1.71-1.58 (m, 4H), 1.57-1.40 (m, 6H), 1.37-1.29(m, 1H), 0.92 (d, 6H).

Example 2115-(3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-[1,2,4]oxadiazol-5-ylmethyl)-imidazolidine-2,4-dione(compound 1233)

General procedure L was followed using(2,5-dioxo-imidazolidin-4-yl)-acetyl chloride. ¹H NMR (600 MHz, DMSO) δ10.83 (br s, 1H), 8.36 (d, 1H), 8.05 (d, 1H), 7.94 (dd, 1H), 7.83 (d,2H), 7.80 (d, 1H), 7.77 (d, 1H), 7.56-7.48 (m, 3H), 7.21 (d, 2H), 4.74(q, 1H), 4.59-4.56 (m, 1H), 3.43 (dd, 1H), 3.38 (dd, 1H), 3.08-3.02 (m,1H), 2.92-2.88 (m, 1H), 1.93-1.83 (m, 1H), 1.82-1.73 (m, 2H), 1.71-1.65(m, 1H), 1.58-1.40 (m, 6H), 1.36-1.29 (m, 1H).

Example 212(3-{4-[5-(4-Methyl-oxazol-5-yl]-[1,2,4]oxadiazol-3-yl-phenyl}-cyclohexyl)-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1234)

General procedure L was followed using 4-methyl-oxazole-5-carbonylchloride. ¹H NMR (600 MHz, DMSO) δ 8.75 (s, 1H), 8.36 (d, 1H), 7.97-7.89(m, 3H), 7.79 (d, 1H), 7.77 (d, 1H), 7.56-7.48 (m, 3H), 7.25 (d, 2H),4.75-4.69 (m, 1H), 3.11-3.04 (m, 1H), 2.92-2.87 (m, 1H), 2.58 (s, 3H),1.89 (dd, 1H), 1.78 (s, 2H), 1.68 (d, 1H), 1.57-1.40 (m, 6H), 1.32 (t,1H).

Example 213(3-{4-[5-(2,5-Dimethyl-oxazol-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-cyclohexyl)-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1235)

General procedure L was followed using 2,5-dimethyl-oxazole-4-carbonylchloride. ¹H NMR (600 MHz, DMSO) δ 8.36 (d, 1H), 7.94 (dd, 1H), 7.90 (d,2H), 7.79 (d, 1H), 7.77 (d, 1H), 7.56-7.48 (m, 3H), 7.23 (d, 2H), 4.71(q, 1H), 3.11-3.02 (m, 1H), 2.91-2.86 (m, 1H), 2.73 (s, 3H), 2.49 (s,3H), 1.94-1.84 (m, 1H), 1.82-1.74 (m, 2H), 1.71-1.65 (m, 1H), 1.57-1.40(m, 6H), 1.36-1.27 (m, 1H).

General Procedure M.

To a solution of cycloalkenone (400 μmol) in 400 μL DME were addedboronic acid (480 μmol, 1.2 eq.), (COD)Rh(1,4-dihydroquinone)BF₄ (1 mol%) in 100 pt DME, and LiOH (4 mol %) in 600 μL water. After shaking themixture overnight at 50° C., the solvent was removed in vacuo. The crudeintermediate ketone was dissolved in DCE containing acetic acid (1.2eq.). (+)-(R)-1-naphthalen-1-yl-ethylamine (1 eq.) in DCE was addedfollowed by NaBH(OAc)₃ (1.2 eq.) The mixture was shaken overnight at r.t., filtered and the solvents were removed in vacuo. The residue wasredissolved in 750 μL DMSO and purified by HPLC.

Example 2142-Methyl-2-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-propionitrile(compound 1236/1237)

General procedure M was followed using4-(2-cyanopropan-2-yl)phenylboronic acid and 2-cyclohexen-1-one. Thetitle compounds were purified by chromatography on 20 g silica gel in agradient from 0 to 60% EtOAc in n-heptane, flow rate 30 mL/min. Compound1236 (1 isomer, less polar, RT˜11 min): ¹³C NMR (75 MHz, DMSO) δ 146.84,142.38, 138.59, 133.47, 130.84, 128.60, 127.05, 126.42, 125.62, 125.54,125.15, 124.80, 124.69, 123.04, 122.94, 50.88, 49.99, 38.75, 36.56,36.17, 33.17, 28.94, 28.26, 24.52, 20.25. Compound 1237 (1 isomer, morepolar, RT˜13 min): ¹³C NMR (75 MHz, DMSO) δ 146.76, 142.14, 138.61,133.39, 130.84, 128.55, 127.18, 126.39, 125.62, 125.50, 125.10, 124.85,124.66, 122.92, 122.80, 50.11, 49.30, 36.44, 36.28, 36.15, 33.36, 30.74,28.24, 24.40, 20.50.

Example 2152-Methyl-2-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-propionicacid (compound 1238)

To a solution of2-methyl-2-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-propionitrile(compound 1236) in MeOH (0.09 M, y mL) was added 28% aq NaOH (y/2 mL).The mixture was heated to reflux over a period of 3 days. MeOH wasremoved under reduced pressure. The residue was taken in water and 4Naq. HCl was added until pH=5. The precipitate was collected, washed withwater and dried in vacuo to afford the title compound. ¹³C NMR (126 MHz,DMSO) δ 177.53, 145.26, 142.13, 133.45, 130.83, 128.58, 126.44, 126.38,125.63, 125.53, 125.22, 125.15, 123.03, 122.92, 50.77, 49.95, 45.22,38.78, 36.48, 33.22, 28.88, 26.29, 24.40, 20.25.

Example 2162-Methyl-2-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-propionicacid (compound 1239)

To a solution of2-methyl-2-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-propionitrile(compound 1237) in MeOH (0.09 M, y mL) was added 28% aq NaOH (y/2 mL).The mixture was heated to reflux over a period of 3 days. MeOH wasremoved under reduced pressure. The residue was taken in water and 4Naq. HCl was added until pH=5. The precipitate was collected, washed withwater and dried in vacuo to afford the title compound. ¹H NMR (600 MHz,DMSO) δ 8.31 (d, 1H), 7.94 (d, 1H), 7.85-7.73 (m, 2H), 7.52 (t, 3H),7.22-6.99 (m, 4H), 5.10-4.53 (m, 1H), 3.05 (br t, 1H), 2.84 (br s, 1H),1.90-1.26 (m, 17H).

Example 217[3-(4-Methanesulfonyl-phenyl)-cyclohexyl]-((R)-1-naphthalen-1-yl-ethyl)-amine(compounds 1240)

General procedure M was followed using4-(methanesulfonyl)-benzeneboronic acid and 2-cyclohexen-1-one. Compound1240 (1 isomer): LC-MS (method B): RT=4.14, [M+H]⁺=408.1. ¹H NMR (600MHz, DMSO) δ 8.30 (d, 1H), 7.96-7.88 (m, 1H), 7.80 (d, 2H), 7.77 (d,1H), 7.72 (d, 1H), 7.55-7.44 (m, 5H), 4.71 (q, 1H), 3.18 (s, 3H),3.23-3.15 (m, 1H), 2.82 (s, 1H), 1.86-1.73 (m, 3H), 1.64-1.56 (m, 1H),1.51-1.34 (m, 7H).

Example 2182-Fluoro-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid methyl ester (compound 1241)

General procedure M was followed using3-fluoro-4-(methoxycarbonyl)-benzeneboronic acid and 2-cyclohexen-1-one.Compound 1241: (1 isomer): LC-MS (method B): RT=4.44, [M+H]⁺=406.1. ¹HNMR (600 MHz, DMSO) δ 8.30 (d, 1H), 7.93-7.89 (m, 1H), 7.77 (dt, 2H),7.72 (d, 1H), 7.52-7.45 (m, 3H), 7.18 (dd, 2H), 4.71 (q, 1H), 3.83 (s,3H), 3.17 (t, 2H), 2.81 (s, 1H), 1.85-1.72 (m, 3H), 1.58 (d, 1H),1.50-1.32 (m, 7H).

Example 219 {4-[3-((R)-1-Naphthalen-1-yl-ethylamino)cyclohexyl]-phenyl}-methanol (compound 1242)

General procedure M was followed using 4-(hydroxymethyl)phenyl boronicacid and 2-cyclohexen-1-one. LC-MS (method B): RT=4.21, [M+H]⁺=360.2(mixture of 2 isomers).

Example 220N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-methanesulfonamide(compound 1243)

General procedure M was followed using(4-methanesulfonylamino-methylphenyl)boronic acid and2-cyclohexen-1-one. Compound 1243 (1 isomer): LC-MS (method B): RT=4.27,[M+H]⁺=437.1. ¹H NMR (600 MHz, DMSO) δ 8.34 (d, 1H), 7.92 (dd, 1H), 7.77(dd, 2H), 7.55-7.47 (m, 3H), 7.44 (t, 1H), 7.16 (d, 2H), 7.01 (d, 2H),4.69 (q, 1H), 4.06 (d, 2H), 2.99-2.91 (m, 1H), 2.88-2.80 (m, 4H),1.90-1.80 (m, 1H), 1.73 (dd, 2H), 1.65-1.60 (m, 1H), 1.51-1.25 (m, 7H).

Example 221{3-[4-(Morpholine-4-sulfonyl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1244/1245)

General procedure M was followed using4-N-morpholinylsulfonyl-phenylboronic acid and 2-cyclohexen-1-one.Compound 1244 (mixture of 2 isomers): LC-MS (method B): RT=4.32,[M+H]⁺=479.2. Compound 1245 (mixture of 2 isomers): LC-MS (method B):RT=4.36, [M+H]⁺=479.1.

Example 222N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-acetamide(compounds 1246/1247)

General procedure M was followed using (4-acetamidomethylphenyl)-boronicacid and 2-cyclohexen-1-one. Compound 1246 (mixture of 2 isomers): LC-MS(method B): RT=4.09, [M+H]⁺=401.1, [M+HCOO]⁻=445.2. Compound 1247(mixture of 3 isomers): LC-MS (method B): RT=4.12, [M+H]⁺=401.1,[M+HCOO]⁻=445.0.

Example 2233-Fluoro-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid methyl ester (compound 1248)

General procedure M was followed using2-fluoro-4-methoxycarbonyl-phenylboronic acid and 2-cyclohexen-1-one.Compound 1248 (mixture of 2 isomers): LC-MS (method B): RT=4.56,[M+H]⁺=406.0.

Example 224N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanesulfonamide(compound 1249/1250)

General procedure M was followed using4-(methanesulfonylamino)-phenylboronic acid and 2-cyclohexen-1-one.Compound 1249 (mixture of 2 isomers): LC-MS (method B): RT=4.24,[M+H]⁺=423.1, [M−H]⁻=421.1. Compound 1250 (mixture of 2 isomers): LC-MS(method B): RT=4.34, [M+H]⁺=423.2, [M−H]⁻=421.0.

Example 225 N-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)cyclohexyl]-phenyl}-methanesulfonamide (compound 1251)

General procedure M was followed using3-(methylsulfonylamino)-phenylboronic acid and 2-cyclohexen-1-one.Compound 1251 (mixture of 2 isomers): LC-MS (method B): RT=4.29,[M+H]⁺=423.1, [M−]⁻=421.0.

Example 226N-(2-Hydroxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzenesulfonamide(compounds 1252/1253)

General procedure M was followed using4-(2-hydroxyethylsulfamoyl)-phenylboronic acid and 2-cyclohexen-1-one.Compound 1252 (mixture of 2 isomers): LC-MS (method B): RT=4.11,[M+H]⁺=453.1, [M−H]⁻=451.0. Compound 1253 (mixture of 4 isomers): LC-MS(method B): RT=4.22, [M+H]⁺=453.1, [M−H]⁺=451.0.

Example 2273-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-propionicacid (compound 1254)

General procedure M was followed using 2-methoxycarbonylethylphenylboronic acid and 2-cyclohexenone. The intermediate ester washydrolyzed following general procedure J. Preparative HPLC afforded thetitle compound as an oil and as a single isomer. LC-MS (method B):RT=4.32, [M+H]⁻=402.1. ¹H NMR (600 MHz, DMSO) δ 8.28 (d, 1H), 7.91 (d,1H), 7.77 (d, 1H), 7.71 (d, 1H), 7.53-7.45 (m, 3H), 7.15-7.00 (m, 4H),4.75-4.66 (m, 1H), 3.05-2.96 (m, 1H), 2.87-2.72 (m, 3H), 1.84-1.67 (m,3H), 1.62-1.54 (m, 1H), 1.47-1.31 (m, 7H). (2 hydrogens hidden underwater signal at 3.2-3.6 ppm)

Example 228{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenoxy}-aceticacid (compound 1255)

General procedure M was followed using4-(2-ethoxy-2-oxoethoxy)-benzeneboronic acid and 2-cyclohexenone. Theintermediate ester was hydrolyzed following general procedure J.Preparative HPLC afforded the title compound as an oil and as a singleisomer. LC-MS (method B): RT=4.22, [M+H]⁺=404.1. ¹H NMR (600 MHz, DMSO)δ 8.29 (d, 1H), 7.92 (d, 1H), 7.78 (d, 1H), 7.76-7.71 (m, 1H), 7.54-7.46(m, 3H), 7.17-6.99 (m, 2H), 6.87-6.64 (m, 2H), 4.79-4.70 (m, 1H),3.06-2.94 (m, 1H), 2.87-2.77 (m, 1H), 1.84-1.67 (m, 3H), 1.62-1.54 (m,1H), 1.50-1.31 (m, 7H).

Example 229[3-(4-Methanesulfonyl-phenyl)-cyclopentyl]-((R)-1-naphthalen-1-yl-ethyl)-amine(compounds 1256/1257)

General procedure M was followed using4-(methanesulfonyl)-benzeneboronic acid and 2-cyclopenten-1-one.Compound 1256 (mixture of 2 isomers): LC-MS (method B): RT=4.22,[M+H]⁺=394.1. Compound 1257 (mixture of 3 isomers): LC-MS (method B):RT=4.24, [M+H]⁺=394.1.

Example 230N-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-methanesulfonamide(compounds 1258/1259)

General procedure M was followed using3-(methylsulfonylamino)-phenylboronic acid and 2-cyclopenten-1-one.Compound 1258 (mixture of 2 isomers): LC-MS (method B): RT=4.27,[M+H]⁺=409.1, [M−H]⁺=407.0. Compound 1259 (mixture of 3 isomers): LC-MS(method B): RT=4.29, [M+H]⁺=409.1, [M−H]⁺=407.1.

Example 231N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-Phenyl}-acetamide(compounds 1260/1261)

General procedure M was followed using 4-acetamidophenylboronic acid and2-cyclopenten-1-one. Compound 1260 (mixture of 2 isomers): LC-MS (methodB): RT=4.16, [M+H]⁺=373.2, [M+HCOO]⁻=417.1. Compound 1261 (mixture ofisomers): LC-MS (method B): RT=4.19, [M+H]⁺=373.2, [M+HCOO]⁻=417.1.

Example 232 N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)cyclopentyl]-benzyl}-acetamide (compound 1262/1263)

General procedure M was followed using (4-acetamidomethylphenyl) boronicacid and 2-cyclopenten-1-one. Compound 1262 (mixture of 2 isomers):LC-MS (method B): RT=4.12, [M+H]⁺=387.1, [M+HCOO]⁻=431.0. Compound 1263(mixture of 4 isomers): LC-MS (method B): RT=4.14, [M+H]⁺=387.1,[M+HCOO]⁻=431.0.

Example 233N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzyl}-methanesulfonamide(compounds 1264/1265)

General procedure M was followed using(4-methanesulfonylamino-methylphenyl)boronic acid and2-cyclopenten-1-one. Compound 1264 (mixture of 2 isomers): LC-MS (methodB): RT=4.24, [M+H]⁺=423.1, [M+HCOO]⁻=467.0. Compound 1265 (mixture of 4isomers): LC-MS (method B): RT=4.27, [M+H]⁺=423.1, [M+HCOO]⁻=467.0.

Example 234N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-methanesulfonamide(compounds 1266/1267)

General procedure M was followed using4-(methanesulfonylamino)-phenylboronic acid and 2-cyclopenten-1-one.Compound 1266 (mixture of 2 isomers): LC-MS (method B): RT=4.26,[M+H]⁺=409.0, [M−H]⁺=407.0. Compound 1267 (mixture of 3 isomers): LC-MS(method B): RT=4.27, [M+H]⁻=409.0, [M−H]⁺=406.9.

Example 235[3-(4-Methanesulfonyl-phenyl)-cycloheptyl]-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1268)

General procedure M was followed using4-(methanesulfonyl)-benzeneboronic acid and 2-cyclohepten-1-one.Compound 1268 (mixture of isomers): LC-MS (method B): RT=4.34,[M+H]⁻=422.1.

Example 2362-Fluoro-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cycloheptyl]-benzoicacid methyl ester (compound 1269)

General procedure M was followed using3-fluoro-4-(methoxycarbonyl)-benzeneboronic acid and2-cyclohepten-1-one. Compound 1269 (mixture of isomers): LC-MS (methodB): RT=4.57, [M+H]⁺=420.1.

Example 237N-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-methanesulfonamide(compound 1270)

General procedure M was followed using3-(methylsulfonylamino)-phenylboronic acid and 2-cyclohepten-1-one.Compound 1270 (mixture of isomers): LC-MS (method B): RT=4.41,[M+H]⁺=437.1, [M−H]⁺=435.0.

Example 238N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-acetamide(compound 1271/1272)

General procedure M was followed using 4-acetamidophenylboronic acid and2-cyclohepten-1-one. Compound 1271 (mixture of isomers): LC-MS (methodB): RT=4.27, [M+H]⁺=401.1, [M+HCOO]⁻=445.2. Compound 1272 (mixture ofisomers): LC-MS (method B): RT=4.32, [M+H]⁺=401.2, [M+HCOO]⁻=445.2.

Example 239N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-benzyl}-acetamide(compounds 1273/1274)

General procedure M was followed using (4-acetamidomethylphenyl)-boronicacid and 2-cyclohepten-1-one. Compound 1273 (mixture of 2 isomers):LC-MS (method B): RT=4.24, [M+H]⁺=415.2, [M+HCOO]⁻=459.1. Compound 1274(mixture of 2 isomers): LC-MS (method B): RT=4.26, [M+H]⁺=415.2,[M+HCOO]⁻=459.2.

Example 240N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-benzyl}-methanesulfonamide(compounds 1275/1276)

General procedure M was followed using(4-methanesulfonylamino-methylphenyl)boronic acid and2-cyclohepten-1-one. Compound 1275 (mixture of isomers): LC-MS (methodB): RT=4.37, [M+H]⁺=451.1, [M+HCOO]⁻=495.2. Compound 1276 (mixture ofisomers): LC-MS (method B): RT=4.39, [M+H]⁺=451.1, [M+HCOO]⁻=495.0.

Example 241{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenoxy}-aceticacid ethyl ester (compound 1277)

General procedure M was followed using4-(2-ethoxy-2-oxoethoxy)-phenylboronic acid and 2-cyclohepten-1-one.Compound 1277 (mixture of 2 isomers): LC-MS (method B): RT=4.66,[M+H]⁺=446.2.

Example 2423-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-propionicacid methyl ester (compounds 1278/1279)

General procedure M was followed using4-(2-methoxycarbonylethyl)-phenylboronic acid and 2-cyclohepten-1-one.Compound 1278 (mixture of 2 isomers): LC-MS (method B): RT=4.66,[M+H]⁺=430.2. Compound 1279 (mixture of 3 isomers): LC-MS (method B):RT=4.66, [M+H]⁺=430.1.

Example 243N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-methanesulfonamide(compounds 1280/1281)

General procedure M was followed using4-(methanesulfonylamino)-phenylboronic acid and 2-cyclohepten-1-one.Compound 1280 (mixture of isomers): LC-MS (method B): RT=4.36,[M+H]⁺=437.1, [M−H]⁻=434.9. Compound 1281 (mixture of isomers): LC-MS(method B): RT=4.37, [M+H]⁺=437.1, [M−H]⁻=434.9.

Example 244{3-[4-(Morpholine-4-sulfonyl)-phenyl]-cycloheptyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1282)

General procedure M was followed using4-(4-morpholinylsulfonyl)-phenylboronic acid and 2-cyclohepten-1-one.Compound 1282 (mixture of isomers): LC-MS (method B): RT=4.47,[M+H]⁺=493.2.

Example 245{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-methanol(compound 1283)

General procedure M was followed using 4-(hydroxymethyl)phenylboronicacid and 2-cyclohepten-1-one. Compound 1283 (mixture of isomers): LC-MS(method B): RT=4.32, [M+H]⁻=374.2.

General Procedure N

To a solution of4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid(compound 1056, 1.5 mmol) in 6 mL dry DMF was added CDI (1.8 mmol).After stirring the solution for 4 hours at r.t., an alcohol (22 mmol, 15eq.) was added, and stirring was continued overnight at r.t. The solventwas removed under reduced pressure, and the residue was purified bychromatography.

Example 246 4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid methyl ester (compound 1284)

General procedure N was followed using methanol. Chromatography(CH₂Cl₂-MeOH 100:0 to 95:5) afforded the title compound. ¹³C NMR (75MHz, DMSO) δ 166.13, 153.14, 147.17, 142.50, 133.54, 130.88, 129.04,128.64, 126.99, 126.48, 125.66, 125.60, 125.20, 123.16, 123.03, 51.86,51.24, 50.22, 38.57, 37.15, 32.82, 29.04, 24.64, 20.26.

Example 247 4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid ethyl ester (compound 1285)

General procedure N was followed using ethanol. Chromatography(CH₂Cl₂-MeOH 100:0 to 97:3) afforded the title compound as an oil. ¹³CNMR (75 MHz, DMSO) δ 165.58, 153.03, 142.44, 133.50, 130.85, 128.97,128.60, 127.26, 126.90, 126.44, 125.61, 125.55, 125.16, 123.11, 122.98,60.35, 51.16, 50.15, 38.51, 37.12, 32.85, 28.98, 24.59, 20.21, 14.10.

Example 248 4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid 2-morpholin-4-yl-ethyl ester dihydrochloride (compound 1286)

General procedure N was followed using N-(2-hydroxyethyl)-morpholine.Chromatography (CH₂Cl₂-MeOH 100:0 to 97:3) afforded an oil, which wasdissolved in ethyl acetate and treated with HCl in dioxane (4 M) anddiethyl ether. The precipitate was filtered to afford the titlecompound. ¹³C NMR (75 MHz, DMSO) δ 165.07, 150.89, 133.85, 133.32,130.24, 129.60, 128.92, 128.84, 126.99, 126.89, 126.09, 125.50, 124.80,122.29, 63.07, 58.87, 54.40, 51.88, 51.25, 50.42, 35.91, 33.45, 30.81,25.66, 20.94, 19.28.

Example 249 4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid 2-(2-methoxy-ethoxy)-ethyl ester hydrochloride (compound 1287)

General procedure N was followed using diethylene glycol monomethylether. Chromatography (CH₂Cl₂-MeOH 100:0 to 80:20) afforded an oil,which was dissolved in ethyl acetate and treated with HCl in dioxane (4M) and diethyl ether. The precipitate was filtered to afford the titlecompound. ¹H NMR (300 MHz, DMSO) δ 9.54 (br m, 2H), 8.35 (d, 1H), 8.20(d, 1H), 8.03-7.94 (m, 2H), 7.85 (d, 2H), 7.60 (dt, 3H), 7.32 (d, 2H),5.56-5.42 (m, 1H), 4.41-4.34 (m, 2H), 3.78-3.70 (m, 2H), 3.59 (dd, 2H),3.46 (dd, 2H), 3.36-3.26 (m, 1H), 3.24 (s, 3H), 3.19-3.07 (m, 1H),2.12-1.37 (m, 11H).

Example 250 4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester hydrochloride (compound1288)

General procedure N was followed using triethylene glycol monomethylether. Chromatography (CH₂Cl₂-MeOH 100:0 to 80:20) afforded an oil,which was dissolved in ethyl acetate and treated with HCl in dioxane (4M) and diethyl ether. The precipitate was filtered to afford the titlecompound. ¹H NMR (300 MHz, DMSO) δ 9.48 (s, 2H), 8.35 (d, 1H), 8.17 (d,1H), 7.99 (t, 2H), 7.86 (d, 2H), 7.62 (dd, 3H), 7.31 (d, 2H), 5.57-5.42(m, 1H), 4.42-4.33 (m, 2H), 3.78-3.70 (m, 2H), 3.62-3.56 (m, 2H),3.55-3.47 (m, 4H), 3.45-3.36 (m, 2H), 3.33-3.26 (m, 1H), 3.20 (s, 3H),3.18-3.08 (m, 1H), 2.11-1.37 (m, 11H).

Example 251 4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid 2-[2-(2-ethoxy-ethoxy)-ethoxy]-ethyl ester hydrochloride (compound1289)

General procedure N was followed using triethylene glycol monoethylether. Chromatography (CH₂Cl₂-MeOH 100:0 to 80:20) afforded an oil,which was dissolved in ethyl acetate and treated with HCl in dioxane (4M) and diethyl ether. The precipitate was filtered to afford the titlecompound. ¹H NMR (300 MHz, DMSO) δ 9.47 (br s, 2H), 8.34 (d, 1H), 8.15(d, 1H), 7.99 (t, 2H), 7.86 (d, 2H), 7.61 (dd, 3H), 7.31 (d, 2H), 5.48(br s, 1H), 4.43-4.33 (m, 2H), 3.79-3.70 (m, 2H), 3.63-3.57 (m, 2H),3.56-3.47 (m, 4H), 3.46-3.21 (m, 5H), 3.20-3.09 (m, 1H), 2.09-1.37 (m,11H), 1.05 (t, 3H).

Example 252 4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid 2,3-dihydroxy-propyl ester hydrochloride (compound 1290)

General procedure N was followed using D-α,β-isopropylidene glycerol.The intermediate acetonide was purified by chromatography (CH₂Cl₂-MeOH100:0 to 80:20) to afford an oil, which was dissolved in EtOAc andtreated with HCl in dioxane (4 M). After the addition of diethyl ether,the precipitate was filtered to afford the title compound. ¹³C NMR (75MHz, DMSO) δ 165.53, 150.34, 133.82, 133.32, 130.24, 129.28, 128.91,127.63, 127.01, 126.88, 126.09, 125.49, 124.70, 122.28, 69.28, 66.11,62.51, 51.93, 50.42, 35.89, 33.40, 30.81, 25.80, 20.83, 19.29.

Example 253 4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid tetrahydro-furan-2-ylmethyl ester hydrochloride (compound 1291)

General procedure N was followed using tetrahydrofurfuryl alcohol.Chromatography (CH₂Cl₂-MeOH 100:0 to 80:20) afforded an oil, which wasdissolved in ethyl acetate and treated with HCl in dioxane (4 M) anddiethyl ether. The precipitate was filtered to afford the titlecompound. ¹H NMR (300 MHz, DMSO) δ 9.45 (br s, 2H), 8.35 (d, 1H), 8.16(d, 1H), 7.99 (t, 2H), 7.85 (d, 2H), 7.61 (dt, 3H), 7.32 (d, 2H),5.56-5.42 (m, 1H), 4.31-4.10 (m, 3H), 3.79 (dt, 1H), 3.73-3.63 (m, 1H),3.36-3.21 (m, 1H), 3.20-3.08 (m, 1H), 2.12-1.37 (m, 15H).

General Procedure O

[Rh(R-BINAP)(nbd)]BF₄ or [Rh(S-BINAP)(nbd)]BF₄ (Tani, K.; Yamagata, T.;Akutagawa, S.; Kumobayashi, H.; Taketomi, T.; Takaya, H.; Miyashita, A.;Noyori, R.; Otsuka, S. J. Am. Chem. Soc. 1984, 106, 5208) (0.03 mmol)and arylboronic acid (1.5 mmol) were added to a 25 mL-flask containing amagnetic stirring bar and a septum inlet. The flask was flashed withargon and charged with aqueous 1,4-dioxane (6/1, 3 mL). Triethylamine(1.5 mmol) and 2-cyclopenten-1-one (1.0 mmol) were then added. Themixture was stirred for 6 h at 25° C. Brine was added, and the mixturewas extracted with ethyl acetate. If necessary the product was purifiedby chromatography over silica gel.

Preparation 6: 3R-(4-Hydroxy-phenyl)-cyclopentanone

General procedure O was followed using 4-hydroxyphenylboronic acid and[Rh(R-BINAP)(nbd)]BF₄. ¹H NMR (300 MHz, DMSO) δ 9.19 (s, 1H), 7.10 (d,2H), 6.70 (d, 2H), 3.33-3.19 (m, 1H), 2.44 (d, 1H), 2.34-2.14 (m, 4H),1.91-1.76 (m, 1H).

Example 2544-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenol(compound 1292)

General procedure A was followed using3-(4-hydroxy-phenyl)-cyclopentanone (preparation 6). The two resultingdiastereomers were separated by preparative chiral HPLC on a ChiralpakAD-H column 250×20 mm, 5 μm at 25° C., UV detection at 280 nm. Isocraticseparation with n-heptane:ethanol:NEt₃: CH₃COOH (75:25:0.1:0:1); flowrate=17.0 mL/min. Compound 1292: RT=17.15. ¹H NMR (300 MHz, DMSO) δ8.34-8.24 (m, 1H), 7.96-7.87 (m, 1H), 7.82-7.68 (m, 2H), 7.57-7.43 (m,3H), 7.03-6.94 (m, 2H), 6.67-6.59 (m, 2H), 4.67 (q, 1H), 3.05-2.93 (m,1H), 2.80-2.66 (m, 1H), 2.13-1.99 (m, 1H), 1.88-1.52 (m, 4H), 1.41-1.22(m, 4H).

General Procedure P:

4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenol(compound 1292) (0.1 mmol) was weighed into a vial and dissolved in 1 mlacetonitrile. To this solution was added alkylbromide or carbamoylchloride (0.12-0.15 mmol) and K₂CO₃ (0.15-0.2 mmol). The vial was sealedand the reaction mixture was heated to 80° C. and stirred for 16 hours.Conversion was checked with LC/MS. The reaction mixture was filteredthrough a pad of celite and concentrated in vacuo. The crude product waspurified by preparative HPLC.

Example 2552-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-butyricacid ethyl ester (compound 1293)

General procedure P was followed using 2-bromo-butanoic acid ethyl esteras alkylbromide. Mixture of 2 isomers. ¹H NMR (300 MHz, DMSO) δ8.33-8.25 (m, 1H), 7.91 (dd, 1H), 7.77 (d, 1H), 7.72 (d, 1H), 7.56-7.44(m, 3H), 7.11 (d, 2H), 6.75 (d, 2H), 4.71-4.61 (m, 2H), 4.13 (q, 2H),3.05-2.93 (m, 1H), 2.85-2.70 (m, 1H), 2.17-2.01 (m, 1H), 1.93-1.55 (m,7H), 1.41-1.26 (m, 4H), 1.18 (t, 3H), 0.96 (t, 3H).

Example 2562-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-butyricacid (compound 1294)

General procedure J was followed using2-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-butyricacid ethyl ester. Mixture of 2 isomers. ¹H NMR (300 MHz, DMSO) δ 8.25(d, 1H), 8.00-7.93 (m, 1H), 7.87 (t, 2H), 7.63-7.48 (m, 3H), 7.09-7.00(m, 1H), 6.97 (d, 1H), 6.75 (dd, 2H), 5.12-4.98 (m, 1H), 4.42-4.33 (m,1H), 3.22-3.06 (m, 1H), 2.83-2.65 (m, 1H), 2.22-2.06 (m, 1H), 2.03-1.42(m, 10H), 0.97 (t, 3H).

Example 2572-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propionicacid (compound 1295)

General procedure P was followed using ethyl 2-bromopropioniate asalkylbromide. The intermediate ester was hydrolyzed following generalprocedure J. Mixture of 2 isomers. ¹H NMR (300 MHz, DMSO) δ 8.24 (d,1H), 8.02-7.74 (m, 3H), 7.63-7.44 (m, 3H), 7.00 (dd, 2H), 6.82-6.64 (m,2H), 5.05-4.88 (m, 1H), 4.60-4.44 (m, 1H), 3.15-2.96 (m, 1H), 2.82-2.63(m, 1H), 2.20-2.02 (m, 1H), 1.96-1.28 (m, 11H).

Example 2583-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-dihydro-furan-2-one(compound 1296)

General procedure P was followed using α-bromo-butyrolactone asalkylbromide.

Mixture of 2 isomers. ¹H NMR (300 MHz, DMSO) δ 8.29 (d, 1H), 7.95 (dd,1H), 7.85 (d, 1H), 7.80-7.75 (m, 1H), 7.62-7.47 (m, 3H), 7.21-7.11 (m,2H), 6.99-6.90 (m, 2H), 5.26 (dd, 1H), 4.87 (q, 1H), 4.42 (td, 1H),4.34-4.22 (m, 1H), 3.17 (dq, 1H), 2.92-2.67 (m, 2H), 2.21 (ddt, 2H),1.96-1.60 (m, 4H), 1.55-1.40 (m, 4H).

Example 259(S)-{3R—[4-(2-Ethoxy-ethoxy)-phenyl]-cyclopentyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1297)

General procedure P was followed using 2-ethoxy-ethylbromide asalkylbromide. ¹H NMR (300 MHz, DMSO) δ 8.33-8.25 (m, 1H), 7.98-7.92 (m,1H), 7.85 (d, 1H), 7.82-7.76 (m, 1H), 7.60-7.48 (m, 3H), 7.15-7.07 (m,2H), 6.87-6.79 (m, 2H), 4.89 (q, 1H), 4.02 (dd, 2H), 3.70-3.63 (m, 2H),3.48 (q, 2H), 3.24-3.11 (m, 1H), 2.89-2.72 (m, 1H), 2.24-2.13 (m, 1H),1.92-1.59 (m, 4H), 1.55-1.41 (m, 4H), 1.12 (t, 3H).

Example 2603-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propionicacid ethyl ester (compound 1298)

General procedure P was followed using ethyl 3-bromopropionate asalkylbromide. ¹H NMR (300 MHz, DMSO) δ 8.29 (d, 1H), 7.94 (dd, 1H), 7.82(d, 1H), 7.77-7.72 (m, 1H), 7.59-7.47 (m, 3H), 7.11 (d, 2H), 6.82 (d,2H), 4.79 (q, 1H), 4.14 (t, 2H), 4.09 (q, 3H), 3.17-3.04 (m, 1H),2.88-2.76 (m, 1H), 2.73 (t, 2H), 2.21-2.08 (m, 1H), 1.92-1.57 (m, 4H),1.49-1.34 (m, 4H), 1.18 (t, 3H).

Example 2614-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxymethyl}-benzonitrile(compound 1299)

General procedure P was followed using 4-cyano-benzylbromide asalkylbromide. ¹H NMR (300 MHz, DMSO) δ 8.29 (d, 1H), 7.93 (dd, 1H),7.89-7.78 (m, 3H), 7.75 (d, 1H), 7.62 (d, 2H), 7.58-7.46 (m, 3H), 7.13(d, 2H), 6.90 (d, 2H), 5.18 (s, 2H), 4.78 (q, 1H), 3.16-3.03 (m, 1H),2.89-2.71 (m, 1H), 2.19-2.07 (m, 1H), 1.91-1.57 (m, 4H), 1.47-1.33 (m,4H).

Example 262(S)—((R)-1-Naphthalen-1-yl-ethyl)-{3R-[4-(pyridin-3-ylmethoxy)-phenyl]-cyclopentyl}-amine(compound 1300)

General procedure P was followed using 3-(bromomethyl)pyridinehydrobromide as alkylbromide. ¹H NMR (300 MHz, DMSO) δ 8.65 (d, 1H),8.53 (dd, 1H), 8.29 (d, 1H), 7.97-7.90 (m, 1H), 7.88-7.79 (m, 2H), 7.75(d, 1H), 7.59-7.47 (m, 3H), 7.44-7.38 (m, 1H), 7.14 (d, 2H), 6.93 (d,2H), 5.10 (s, 2H), 4.79 (q, 1H), 3.16-3.04 (m, 1H), 2.89-2.71 (m, 1H),2.21-2.08 (m, 1H), 1.91-1.56 (m, 4H), 1.48-1.34 (m, 4H).

Example 263(S)—((R)-1-Naphthalen-1-yl-ethyl)-{3R—[4-(2-pyrazol-1-yl-ethoxy)-phenyl]-cyclopentyl}-amine(compound 1301)

General procedure P was followed using 1-(2-bromoethyl)-1H-pyrrazole asalkylbromide. ¹H NMR (300 MHz, DMSO) δ 8.28 (d, 1H), 7.94 (dd, 1H), 7.82(d, 1H), 7.75 (dd, 2H), 7.59-7.47 (m, 3H), 7.46-7.43 (m, 1H), 7.10 (d,2H), 6.79 (d, 2H), 6.23 (t, 1H), 4.81 (q, 1H), 4.46 (t, 2H), 4.27 (t,2H), 3.19-3.05 (m, 1H), 2.88-2.70 (m, 1H), 2.21-2.08 (m, 1H), 1.92-1.55(m, 4H), 1.49-1.32 (m, 4H).

Example 264(S)-(3R-{4-[2-(1H-Indol-3-yl)-ethoxy]-phenyl}-cyclopentyl)-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1302)

General procedure P was followed using 3-(2-bromoethyl)-indole asalkylbromide. ¹H NMR (300 MHz, DMSO) δ 10.86 (s, 1H), 8.29 (d, 1H),7.97-7.91 (m, 1H), 7.82 (d, 1H), 7.75 (d, 1H), 7.61-7.46 (m, 4H), 7.34(d, 1H), 7.23 (d, 1H), 7.15-6.94 (m, 4H), 6.85 (d, 2H), 4.81 (q, 1H),4.16 (t, 2H), 3.17-3.06 (m, 3H), 2.88-2.71 (m, 1H), 2.21-2.09 (m, 1H),1.92-1.56 (m, 4H), 1.49-1.35 (m, 4H).

Example 2652-Methyl-2-{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propionicacid hydrochloride (compound 1303)

General procedure P was followed using ethyl 2-bromo-2-methylpropionateas alkylbromide. The intermediate ester was hydrolyzed following generalprocedure J to the neutral acid. The neutral acid was dissolved in ethylacetate and treated with HCl in dioxane (4 M) and diethyl ether. Theprecipitate was filtered to afford the title compound. ¹H NMR (300 MHz,DMSO) δ 12.96 (br s, 1H), 10.18-10.02 (br s, 1H), 9.49-9.33 (br s, 1H),8.30 (d, 1H), 8.08-7.94 (m, 3H), 7.69-7.54 (m, 3H), 7.12 (d, 2H), 6.75(d, 2H), 5.38-5.24 (m, 1H), 3.53-3.43 (m, 1H), 2.98-2.79 (m, 1H),2.46-2.32 (m, 1H), 2.20-2.04 (m, 1H), 1.97-1.65 (m, 7H), 1.47 (s, 6H).

Example 2664-Hydroxy-2-{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-butyricacid (compound 1304)

General procedure J was followed using3-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-dihydro-furan-2-one(compound 1296). Mixture of 2 isomers. ¹H NMR (300 MHz, DMSO) δ 8.24 (d,1H), 8.02-7.94 (m, 1H), 7.93-7.82 (m, 2H), 7.63-7.49 (m, 3H), 7.08-6.90(m, 2H), 6.80-6.67 (m, 2H), 5.16-5.02 (m, 1H), 4.58-4.47 (m, 1H),3.66-3.50 (m, 2H), 3.22-3.08 (m, 2H), 2.83-2.65 (m, 1H), 2.22-1.84 (m,4H), 1.81-1.44 (m, 7H).

Example 2672-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propionicacid hydrochloride (compound 1305)

General procedure P was followed using ethyl 2-bromopropioniate asalkylbromide. The intermediate ester was hydrolyzed following generalprocedure J to the neutral acid. The neutral acid was dissolved in ethylacetate and treated with HCl in dioxane (4 M) and diethyl ether. Theprecipitate was filtered to afford the title compound as a mixture oftwo isomers. ¹H NMR (300 MHz, DMSO) δ 9.65 (br s, 1H), 9.27 (br s, 1H),8.30 (d, 1H), 8.02 (t, 2H), 7.93 (d, 1H), 7.71-7.56 (m, 3H), 7.13 (d,2H), 6.80 (d, 2H), 5.40-5.25 (m, 1H), 4.83-4.71 (m, 1H), 3.63-3.45 (m,1H), 2.92 (s, 1H), 2.53-2.35 (m, 1H), 2.14-1.85 (m, 3H), 1.73 (t, 5H),1.47 (d, 3H).

Example 268{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-phenyl-aceticacid hydrochloride (compound 1306)

General procedure P was followed using ethyl bromophenylacetate asalkylbromide. The intermediate ester was hydrolyzed using generalprocedure J. The product was dissolved in ethyl acetate and treated withHCl in dioxane (4 M) and diethyl ether. The precipitate was filtered toafford the title compound as a mixture of 2 isomers. ¹H NMR (300 MHz,DMSO) δ 9.65 (br s, 1H), 9.27 (br s, 1H), 8.30 (d, 1H), 8.07-7.97 (m,2H), 7.93 (d, 1H), 7.70-7.56 (m, 3H), 7.13 (d, 2H), 6.80 (d, 2H),5.39-5.26 (m, 1H), 4.75 (q, 1H), 3.62-3.47 (m, 1H), 2.92 (s, 1H),2.51-2.36 (m, 1H), 2.13-1.85 (m, 3H), 1.80-1.63 (m, 5H), 1.47 (d, 3H).

Example 2692-Methyl-1-{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propan-2-ol(compound 1307)

To a solution of{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid ethyl ester (compound 1180) (150 mg, 360 μmol) in dry THF (2 mL)was added methylmagnesium bromide (3.0 M in THF, 0.6 mL) at −78° C.After stirring for 5 hours at this −78-−40° C., the reaction mixture wasquenched with aqueous NaHCO₃ and extracted with ethyl acetate. Theorganic fase was concentrated in vacuo and purified by HPLC to affordthe title compound. ¹³C NMR (75 MHz, DMSO) δ 157.00, 141.09, 137.34,133.38, 130.78, 128.60, 127.59, 126.74, 125.76, 125.53, 125.25, 123.13,122.83, 114.20, 76.07, 68.52, 56.45, 51.23, 42.52, 41.92, 32.12, 31.41,26.53, 23.65.

Example 2703-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxymethyl}-pentan-3-ol(compound 1308)

To a solution of{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid ethyl ester (compound 1180) (150 mg, 360 μmol) in dry THF (2 mL)was added ethylmagnesium bromide (1.0 M in THF, 718 μL) at −78° C. Afterstirring for 2.5 hours at this temperature, additional ethylmagnesiumbromide was added (360 μL), and the reaction mixture was stirred foranother hour before quenching with aqueous NaHCO₃ and extracting withethyl acetate. The organic fase was concentrated in vacuo and purifiedby HPLC to afford the title compound. ¹³C NMR (75 MHz, DMSO) δ 156.92,142.08, 137.61, 133.39, 130.88, 128.56, 127.60, 126.44, 125.59, 125.53,125.12, 122.96, 122.91, 114.14, 72.12, 71.80, 56.60, 51.34, 42.54,42.47, 32.21, 31.89, 28.68, 24.18, 7.40.

Example 271 Dimethyl-carbamic acid4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenylester (compound 1309)

General procedure P was followed using N,N-dimethylcarbamoyl chloride.¹H NMR (300 MHz, DMSO) δ 8.30 (d, 1H), 7.91 (dd, 1H), 7.75 (dd, 2H),7.57-7.43 (m, 3H), 7.21 (d, 2H), 6.97 (d, 2H), 4.67 (q, 1H), 3.02 (s,3H), 2.89 (s, 4H), 2.18-2.06 (m, 1H), 1.93-1.58 (m, 4H), 1.47-1.30 (m,4H). A signal (1H) is presumably hidden under the water signal at 3.32ppm.

Example 2723-Ethyl-1-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-pentan-3-ol(compound 1310)

To a solution of3-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid methyl ester (compound 1183) (150 mg) in dry THF (2 mL) was slowlyadded ethylmagnesium bromide (1.8 mL of a 1.0 M solution in THF) at −78°C. The reaction mixture was stirred for 5 hours while slowly warming to−40° C. Ethyl acetate was added to the mixture, and the product waspurified by HPLC. ¹H NMR (300 MHz, DMSO) δ 8.30 (d, 1H), 7.97-7.89 (m,1H), 7.81 (d, 1H), 7.75 (d, 1H), 7.59-7.46 (m, 3H), 7.03 (s, 4H), 4.75(q, 1H), 3.27-3.10 (m, 2H), 2.50-2.38 (m, 2H), 2.09-1.79 (m, 3H),1.70-1.46 (m, 4H), 1.45-1.30 (m, 8H), 0.79 (t, 6H).

Example 2732-Methyl-4-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-butan-2-ol(compound 1311)

To a solution of3-{4-[(3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid methyl ester (compound 1183) (150 mg) in dry THF (2 mL) was addedmethyl magnesiumbromide (0.6 mL of a 3M solution in THF) at −78° C. Thereaction mixture was stirred for 5 hours while slowly warming to −40° C.Ethyl acetate (0.5 mL) was added, and the mixture was purified by HPLCto afford the title compound. ¹³C NMR (75 MHz, DMSO) δ 142.76, 141.00,140.11, 133.40, 130.77, 128.63, 127.90, 126.81, 126.63, 125.81, 125.54,125.29, 123.19, 122.84, 68.54, 56.20, 50.83, 45.71, 42.42, 40.71, 33.17,32.65, 29.68, 29.17, 23.61.

Example 2743-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propane-1,2-diol(compound 1312)

General procedure P was followed using 3-bromo-propane-1,2-diol asalkylbromide. Compound 1312 (mixture of 2 isomers): LC-MS (method A):RT=2.44, [M+H]⁺=406.5.

Example 275(2-Fluoro-phenyl)-{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid hydrochloride (compound 1313)

General procedure P was followed using bromo-(2-fluoro-phenyl)-aceticacid methyl ester as alkylbromide. The intermediate ester was hydrolyzedfollowing general procedure J to the neutral acid. The neutral acid wasdissolved in ethyl acetate and treated with HCl in dioxane (4 M) anddiethyl ether. The precipitate was filtered to afford the title compoundas a mixture of 2 isomers. ¹H NMR (300 MHz, DMSO) δ 8.29 (d, 1H), 8.12(d, 1H), 8.04-7.94 (m, 2H), 7.67-7.50 (m, 4H), 7.48-7.36 (m, 1H),7.30-7.19 (m, 2H), 7.14 (d, 2H), 6.88 (d, 2H), 5.89 (s, 1H), 5.35-5.22(m, 1H), 4.53-4.42 (m, 1H), 2.94-2.79 (m, 1H), 2.41-2.09 (m, 2H),1.91-1.67 (m, 7H).

Example 2762-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-ethanolformiate (compound 1314)

To a solution of{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid ethyl ester (compound 1180) (180 mg) in dry diethyl ether (3 mL)was added LiAlH₄ (0.52 mL of a 1M solution in THF) at 0° C. After 30min, the reaction was quenched with water and purified by preparativeHPLC to afford the title compound as an oil. ¹H NMR (300 MHz, DMSO) δ8.33-8.24 (m, 2H), 7.98-7.92 (m, 1H), 7.85 (d, 1H), 7.78 (d, 1H),7.61-7.48 (m, 3H), 7.11 (d, 2H), 6.82 (d, 2H), 4.88 (q, 1H), 3.93 (t,2H), 3.69 (t, 2H), 3.23-3.11 (m, 1H), 2.88-2.73 (m, 1H), 2.19 (dt, 1H),1.92-1.59 (m, 4H), 1.55-1.40 (m, 4H).

Preparation 7: 4-(3-Oxo-cyclohexyl)-benzaldehyde

General procedure K was followed using 4-formylphenylboronic acid. ¹³CNMR (75 MHz, DMSO) δ 209.52, 192.53, 151.70, 134.67, 129.75, 127.46,47.42, 43.72, 40.32, 31.66, 24.80.

General Procedure Q

To a solution of 4-(3-oxo-cyclohexyl)-benzaldehyde (0.082 mmol) in DCE(1 mL) were added an amine (165 μL of a 0.5 mM solution in DCE) andNaBH(OAc)₃ (0.24 mmol, 3 eq.). After shaking the reaction mixtureovernight at r.t., (+)-(R)-1-naphthalen-1-yl-ethylamine (0.090 mmol) in0.5 mL DCE was added, and shaking was continued overnight at r.t.Solvents were removed in vacuo. The residue was redissolved in DMSO andpurified by preparative HPLC.

Example 277(1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-pyrrolidin-2-yl)-methanol(compound 1315)

General procedure Q was followed using(S)-(+)-2-(hydroxymethyl)-pyrrolidine. LC-MS (method B): RT=3.67,[M+HCOO]⁻=487.3.

Example 2781-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-pyrrolidin-3-ol(compound 1316)

General procedure Q was followed using (R)-3-hydroxypyrrolidine. LC-MS(method B): RT=3.67, [M+H]⁺=429.2.

Example 2791-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-piperidine-3-carboxylicacid ethyl ester (compound 1317)

General procedure Q was followed using piperidine-3-carboxylic acidethyl ester. LC-MS (method B): RT=3.86, [M+H]⁺=499.3.

Example 280[3-(4-{[Methyl-(tetrahydro-furan-2-ylmethyl)-amino]-methyl}-phenly)-cyclohexyl]-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1318)

General procedure Q was followed using N-methyltetrahydrofurfurylamine.LC-MS (method B): RT=3.76, [M+H]⁺=457.3,

Preparation 8: 3-[4-((1S)-3-Oxo-cyclopentyl)-phenyl]-propionic acidethyl ester

General procedure O was followed using[4-(2-ethoxycarbonylethyl)-phenyl]-boronic acid and[Rh(S-BINAP)(nbd)]BF₄. ¹H NMR (300 MHz, DMSO) δ 7.26-7.20 (m, 2H),7.19-7.13 (m, 2H), 4.04 (q, 2H), 3.43-3.24 (m, 1H), 2.82 (t, 2H),2.63-2.45 (m, 3H), 2.35-2.21 (m, 4H), 1.96-1.77 (m, 1H), 1.15 (t, 3H).

Preparation 9: 3-[4-((1S,3R)-3-Acetoxy-cyclopentyl)-phenyl]-propionicacid ethyl ester

To a solution of 3-[4-(3-oxo-cyclopentyl)-phenyl]-propionic acid ethylester

(preparation 8) (26.2 g, 100 mmol) in ethanol (300 mL) was added NaBH₄(5.7 g, 151 mmol) in portions. The mixture was stirred at r.t. for 1hour, and then the solvent was removed in vacuo. Water was added to theresidue and the mixture was extracted multiple times withdichloromethane. The combined organic extracts were dried over MgSO₄ andconcentrated in vacuo. To the crude cyclopentanol (25.7 g, 98.0 mmol) indry n-hexane (340 mL) were added vinyl acetate (340 mL, 50 eq.),molecular sieves (4 Å) and PPL (lipase from hog pancreas, EC 3.1.1.3,30.1 U/mg, 20 g). The mixture was stirred under argon for 2 hours,filtered through Celite and concentrated under reduced pressure.Chromatography (EtOAc-PE 0:100 to 50:50) and collection of the lesspolar fractions afforded the title compound as an oil. ¹H NMR (300 MHz,DMSO) δ 7.20-7.09 (m, 4H), 5.16-5.06 (m, 1H), 4.04 (q, 2H), 3.09-2.94(m, 1H), 2.80 (t, 2H), 2.58 (t, 2H), 2.52-2.39 (m, 1H), 2.04-1.51 (m,8H), 1.15 (t, 3H).

Preparation 10: 3-[4-((1S,3R)-3-Hydroxy-cyclopentyl)-phenyl]-propionicacid ethyl ester

To a solution of 3-[4-(3-acetoxy-cyclopentyl)-phenyl]-propionic acidethyl ester (preparation 9) (23.1 g, 75.9 mmol) in dry ethanol (1.1 l)under argon was added K₂CO₃ (31.5 g, 228 mmol). The mixture was heatedat 50-60° C. for 3 hours, then filtered through Celite and concentratedunder reduced pressure. The residue was suspended in water and extractedwith dichloromethane. The organic phase was dried over MgSO₄, filtered,and concentrated under reduced pressure. The crude product was usedwithout further purification. ¹H NMR (300 MHz, DMSO) δ 7.17 (d, 2H),7.11 (d, 2H), 4.61-4.56 (m, 1H), 4.24-4.14 (m, 1H), 4.04 (q, 2H),2.99-2.85 (m, 1H), 2.80 (t, 2H), 2.57 (t, 2H), 2.32-2.19 (m, 1H),1.96-1.58 (m, 4H), 1.52-1.38 (m, 1H), 1.20-1.10 (m, 3H).

Preparation 11:3-[4-((1S,3R)-3-Methanesulfonyloxy-cyclopentyl)-phenyl]-propionic acidethyl ester

To a solution of 3-[4-(3-hydroxy-cyclopentyl)-phenyl]-propionic acidethyl ester (preparation 10) (3.16 g, 12.1 mmol) in dry CH₂Cl₂ (30 mL)under argon were added NEt₃ (3.66 g, 36.1 mmol) andmethanesulfonylchloride (1.38 g, 24.1 mmol) at 0° C. After stirring theresulting solution for 1 hour at 0° C., the reaction was quenched withwater and extracted with CH₂Cl₂. The organic phase was dried over MgSO₄,filtered and concentrated under reduced pressure. The crude product wasused immediately without further purification. ¹H NMR (300 MHz, DMSO) δ7.21-7.09 (m, 4H), 5.22-5.13 (m, 1H), 4.04 (q, 2H), 3.17 (s, 3H),3.13-2.93 (m, 1H), 2.81 (t, 2H), 2.63-2.52 (m, 3H), 2.08-1.93 (m, 3H),1.86-1.61 (m, 2H), 1.15 (t, 3H).

General Procedure R

To a suspension of3-[4-(3-methanesulfonyloxy-cyclopentyl)-phenyl]-propionic acid ethylester (preparation 11) (1.20 mmol) in propionitrile (3 mL) were addedK₂CO₃ (3.6 mmol) and amine (1.20 mmol), and the reaction mixture washeated at 80° C. overnight. The mixture was filtered, and the filtratewas concentrated under reduced pressure. The product was purified bypreparative HPLC, 10→80% ethyl acetate in hexanes.

Example 2813-(4-{(1S,3S)-3-[(R)-1-(4-Fluoro-3-methoxy-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid ethyl ester (compound 1319)

General procedure R was followed using1-(4-fluoro-3-methoxy-phenyl)-ethylamine. ¹H NMR (300 MHz, DMSO) δ 7.22(dd, 1H), 7.10 (m, 5H), 6.94 (m, 1H), 4.03 (q, 2H), 3.85 (m, 4H), 3.15(m, 2H), 2.78 (t, 2H), 2.56 (t, 2H), 1.99 (m, 2H), 1.78 (m, 1H),1.70-1.35 (m, 3H), 1.30 (d, 3H), 1.14 (t, 3H).

Example 2823-(4-{(1S,3S)-3-[(R)-1-(3-Cyano-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid ethyl ester (compound 1320)

General procedure R was followed using 1-(3-cyano-phenyl)-ethylamine. ¹HNMR (300 MHz, DMSO) δ 7.82 (s, 1H), 7.69 (m, 2H), 7.52 (t, 1H), 7.07 (m,4H), 4.03 (q, 2H), 3.82 (q, 1H), 3.15 (m, 1H), 2.98 (m, 1H), 2.78 (t,2H), 2.55 (t, 2H), 2.01 (m, 1H), 1.91 (m, 1H), 1.70 (ddd, 1H), 1.57 (m,1H), 1.45 (m, 2H), 1.25 (d, 3H), 1.14 (t, 3H).

Example 2833-{4-[(1S,3S)-3-((R)-1-Benzo[b]thiophen-3-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid ethyl ester (compound 1321)

General procedure R was followed using1-benzo[b]thiophen-3-yl-ethylamine. ¹H NMR (300 MHz, DMSO) δ 8.03 (dd,1H), 7.97 (dd, 1H), 7.65 (s, 1H), 7.38 (m, 2H), 7.08 (m, 4H), 4.36 (q,1H), 4.03 (q, 2H), 3.28 (m, 1H), 3.17 (m, 1H), 2.77 (t, 2H), 2.55 (t,2H), 2.00 (m, 2H), 1.84 (m, 1H), 1.59 (m, 2H), 1.45 (d, 3H), 1.40 (m,1H), 1.14 (t, 3H).

Example 2843-(4-{(1S,3S)-3-[1-((R)-2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid ethyl ester (compound 1322)

General procedure R was followed using1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamine. ¹H NMR (300 MHz, DMSO)δ 7.09 (2, 4H), 6.92 (s, 1H), 6.85 (d, 1H), 6.80 (d, 1H), 4.22 (s, 4H),4.03 (q, 2H), 3.84 (q, 1H), 3.15 (m, 2H), 2.78 (t, 2H), 2.56 (t, 2H),2.00 (m, 2H), 1.85 (m, 1H), 1.68 (m, 1H), 1.56 (m, 1H), 1.45 (m, 1H),1.30 (d, 3H), 1.14 (t, 3H).

Example 2853-{4-[(1S,3S)-3-((R)-1-Phenyl-ethylamino)-cyclopentyl]-phenyl}-propionicacid ethyl ester (compound 1323)

General procedure R was followed using 1-phenyl-ethylamine. ¹H NMR (300MHz, DMSO) δ 7.3 (m, 4H), 7.22 (tt, 1H), 7.07 (dd, 4H), 4.03 (q, 2H),3.82 (q, 1H), 3.15 (m, 1H), 3.05 (m, 1H), 2.77 (t, 2H), 2.55 (t, 2H),2.01 (m, 1H), 1.93 (m, 1H), 1.76 (m, 1H), 1.65-1.35 (m, 3H), 1.29 (d,3H), 1.14 (t, 3H).

Example 2863-(4-{(1S,3S)-3-[(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid ethyl ester (compound 1324)

General procedure R was followed using1-(2,3-dihydro-benzofuran-5-yl)-ethylamine. ¹H NMR (300 MHz, DMSO) δ7.18 (d, 1H), 7.06 (m, 5H), 6.65 (d, 1H), 4.47 (t, 2H), 4.03 (q, 2H),3.66 (q, 1H), 3.14 (m, 3H), 3.00 (m, 1H), 2.78 (t, 2H), 2.56 (t, 2H),2.01 (m, 1H), 1.89 (m, 1H), 1.70 (m, 1H), 1.57 (m, 1H), 1.44 (m, 2H),1.21 (d, 3H), 1.14 (t, 3H).

Example 2873-(4-{(1S,3S)-3-[(R)-1-(1H-Indol-7-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid hydroformiate (compound 1325)

General procedure J was followed using ethyl3-(4-{3-[1-(1H-indol-7-yl)-ethylamino]-cyclopentyl}-phenyl)-propionate.¹H NMR (300 MHz, DMSO) δ 11.20 (s, 1H), 8.32 (s, 1H), 7.46 (d, 1H), 7.35(m, 1H), 7.20 (d, 1H), 7.08 (d, 2H), 7.04 (d, 2H), 7.01 (t, 1H), 6.45(dd, 1H), 4.54 (dd, 1H), 3.23 (m, 1H), 3.18 (m, 1H), 2.74 (t, 2H), 2.46(t, 2H), 2.02 (m, 1H), 1.94 (m, 2H), 1.68 (m, 2H), 1.49 (d, 3H), 1.42(d, 1H).

Example 2883-(4-{(1S,3S)-3-[(R)-1-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid hydroformiate (compound 1326)

General procedure J was followed using ethyl3-(4-{3-[1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamino]-cyclopentyl}-phenyl)-propionate.¹H NMR (300 MHz, DMSO) δ 8.25 (s, 1H), 7.11 (d, 2H), 7.08 (d, 2H), 7.00(dd, 1H), 6.83 (dd, 1H), 6.76 (dd, 1H), 4.28 (m, 2H), 4.23 (m, 2H), 3.20(m, 1H), 3.16 (m, 1H), 2.75 (m, ²H), 2.47 (m, 2H), 2.02 (m, 1H), 1.96(m, 1H), 1.88 (m, 1H), 1.71 (m, 1H), 1.59 (m, 1H), 1.46 (m, 1H), 1.33(d, 3H).

Example 2893-(4-{(1S,3S)-3-[(R)-1-(1H-Indol-4-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid hydroformiate (compound 1327)

General procedure J was followed using ethyl3-(4-{3-[1-(1H-indol-4-yl)-ethylamino]-cyclopentyl}-phenyl)-propionate.¹H NMR (300 MHz, DMSO) δ 11.28 (s, 1H), 8.33 (s, 1H), 7.39 (m, 1H), 7.37(d, 1H), 7.24 (d, 1H), 7.14 (m, 1H), 7.09 (d, 2H), 7.05 (d, 2H), 6.71(m, 1H), 4.61 (q, 1H), 3.28 (m, 1H), 3.23 (m, 1H), 2.75 (t, 2H), 2.47(t, 2H), 2.00 (m, 3H), 1.83 (m, 1H), 1.74 (m, 1H), 1.59 (d, 3H), 1.41(m, 1H).

Example 2903-(4-{(1S,3S)-3-[(R)-1-(3-Cyano-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid, hydroformiate (compound 1328)

General procedure J was followed using ethyl3-(4-{3-[1-(3-cyano-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionate.¹H NMR (300 MHz, DMSO) δ 8.18 (s, 1H), 7.86 (s, 1H), 7.74 (s, 1H), 7.71(d, 1H), 7.55 (t, 1H), 7.09 (d, 2H), 7.06 (d, 2H), 3.92 (q, 1H), 3.15(m, 1H), 3.04 (m, 1H), 2.74 (t, 2H), 2.48 (t, 2H), 2.02 (m, 1H), 1.94(m, 1H), 1.75 (m, 1H), 1.62 (m, 1H), 1.52 (m, 1H), 1.43 (m, 1H), 1.30(d, 3H).

Example 291 3-(4-{(1S,3S)-3-[(R)-1-(3-Pyrrolidin-1-yl-phenyl)ethylamino]-cyclopentyl}-phenyl)-propionic acid hydroformiate (compound1329)

General procedure J was followed using ethyl3-(4-{3-[1-(3-pyrrolidin-1-yl-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionate.¹H NMR (300 MHz, DMSO) 68.26 (2, 1H), 7.07 (m, 4H), 6.60 (d, 1H), 6.55(s, 1H), 6.40 (d, 1H), 3.77 (s, 1H), 3.21 (m, 4H), 3.15 (m, 1H), 3.11(m, 1H), 2.74 (t, 2H), 2.47 (t, 2H), 2.01 (m, 1H), 1.94 (m, 5H), 1.79(m, 1H), 1.64 (m, 1H), 1.53 (m, 1H), 1.43 (m, 1H), 1.29 (d, 3H).

Example 2923-(4-{(1S,3S)-3-[(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid hydroformiate (compound 1330)

General procedure J was followed using ethyl3-(4-{3-[1-(2,3-dihydro-benzofuran-5-yl)-ethylamino]-cyclopentyl}-phenyl)-propionate.¹H NMR (300 MHz, DMSO) 68.23 (s, 1H), 7.24 (s, 1H), 7.08 (m, 5H), 6.69(m, 1H), 4.49 (m, 2H), 3.79 (m, 1H), 3.16 (m, 3H), 3.09 (m, 1H), 2.75(t, 2H), 2.47 (t, 2H), 2.00 (m, 1H), 1.95 (m, 1H), 1.77 (m, 1H), 1.63(m, 1H), 1.52 (m, 1H), 1.44 (m, 1H), 1.27 (d, 3H).

Example 2933-(4-{(1S,3S)-3-[(R)-1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid (compound 1331)

General procedure J was followed using ethyl3-(4-{3-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-cyclopentyl}-phenyl)-propionate.¹H NMR (300 MHz, DMSO) 67.10 (m, 5H), 6.99 (d, 1H), 6.87 (d, 1H), 4.24(m, 4H), 4.09 (m, 1H), 3.26 (m, 2H), 2.76 (t, 2H), 2.48 (t, 2H), 2.04(m, 3H), 1.78 (m 2H), 1.47 (m, 4H).

Example 2943-(4-{(1S,3S)-3-[(R)-1-(4-fluoro-3-methoxy-1-yl-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid (compound 1332)

General procedure J was followed using ethyl3-(4-{3-[1-(4-fluoro-3-methoxy-1-yl-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionate.¹H NMR (300 MHz, DMSO) δ 7.33 (d, 1H), 7.17 (dd, 1H), 7.08 (dd, 4H),6.99 (m, 1H), 3.99 (m, 1H), 3.84 (s, 3H), 3.19 (m, 2H), 2.75 (t, 2H),2.18 (t, 2H), 2.01 (m, 2H), 1.89 (m, 1H), 1.68 (m, 1H), 1.62 (m, 1H),1.44 (m, 1H), 1.38 (d, 3H).

Example 2953-{4-[(1S,3S)-3-((R)-1-Benzo[b]thiophen-3-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid hydrochloride (compound 1333)

General procedure was followed using ethyl3-{4-[3-(1-benzo[b]thiophen-3-yl-ethylamino)-cyclopentyl]-phenyl}-propionate.¹H NMR (300 MHz, DMSO) δ 8.29 (s, 1H), 8.12 (d, 1H), 8.07 (d, 1H), 7.47(ddd, 2H), 7.10 (dd, 4H), 4.94 (q, 1H), 3.52 (m, 1H), 3.31 (m, 1H), 2.19(t, 2H), 2.47 (t, 2H), 2.24 (m, 1H), 2.05 (m, 2H), 1.96 (m, 1H), 1.87(m, 1H), 1.73 (d, 3H), 1.47 (m, 1H).

Example 2963-{4-[(1S,3.5)-3-((R)-1-Phenyl-ethylamino)-cyclopentyl]-phenyl}-propionicacid (compound 1334)

General procedure J was followed using ethyl3-{4-[3-(1-phenyl-ethylamino)-cyclopentyl]-phenyl}-propionate. ¹H NMR(300 MHz, DMSO) δ 7.94 (d, 2H), 7.37 (t, 2H), 7.29 (t, 1H), 7.09 (dd,4H), 3.99 (m, 1H), 3.17 (m, 2H), 2.75 (t, 2H), 2.47 (t, 2H), 2.02 (m,2H), 1.84 (m, 1H), 1.69 (m, 1H), 1.60 (m, 1H), 1.44 (m, 1H), 1.37 (bs,3H).

Preparation 12: 4-(3S-Oxo-cyclopentyl)-benzoic acid ethyl ester

General procedure O was followed using 4-ethoxycarbonylphenylboronicacid and [Rh(S-BINAP)(nbd)]BF₄. ¹H NMR (300 MHz, CDCl3) δ 8.05-7.98 (m,2H), 7.36-7.29 (m, 2H), 4.38 (q, 2H), 3.55-3.40 (m, 1H), 2.75-2.63 (m,1H), 2.55-2.41 (m, 2H), 2.41-2.25 (m, 2H), 2.08-1.92 (m, 1H), 1.39 (t,3H).

Example 297 4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoicacid ethyl ester (compound 1335/1336)

General procedure A was followed using 4-(3S-oxo-cyclopentyl)-benzoicacid ethyl ester (preparation 12) and(+)-(R)-1-naphthalen-1-yl-ethylamine. The two resulting diastereomerswere separated by preparative chiral HPLC on a Chiralpak AD-H column250×20 mm, 5 μm at 25° C., UV detection at 280 nm. Isocratic separationwith n-heptane:ethanol:NEt₃:CH₃COOH (75:25:0.1:0.1); flow rate=17.0mL/min. Compound 1335: RT=8.82. ¹H NMR (300 MHz, DMSO) δ 8.29 (d, 1H),7.95-7.89 (m, 1H), 7.86 (d, 2H), 7.82-7.70 (m, 2H), 7.55-7.44 (m, 3H),7.39 (d, 2H), 4.65 (q, 1H), 4.29 (q, 2H), 3.11-2.88 (m, 2H), 2.41-2.27(m, 1H), 2.26-2.14 (m, 1H), 1.98-1.42 (m, 5H), 1.37 (d, 3H), 1.31 (t,3H). Compound 1336: RT=12.04. ¹H NMR (300 MHz, DMSO) δ 8.30 (d, 1H),7.95-7.88 (m, 1H), 7.85-7.69 (m, 4H), 7.56-7.45 (m, 3H), 7.28 (d, 2H),4.64 (q, 1H), 4.27 (t, 2H), 3.35-3.23 (m, 1H), 3.21-3.11 (m, 1H),2.33-2.20 (m, 1H), 2.17-2.02 (m, 1H), 1.98-1.79 (m, 2H), 1.71-1.41 (m,3H), 1.38 (d, 3H), 1.29 (t, 3H).

Example 298 4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoicacid (compound 1337)

General procedure J was followed using4-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoic acid ethylester (compound 1335). ¹H NMR (500 MHz, DMSO) δ 8.30 (d, 1H), 8.24 (s,1H), 7.94 (d, 1H), 7.82 (t, 3H), 7.76 (d, 1H), 7.52 (dt, 3H), 7.28 (d,2H), 4.80 (q, 1H), 3.37-3.28 (m, 1H), 3.25-3.19 (m, 1H), 2.16-2.09 (m,1H), 2.08-1.95 (m, 2H), 1.66-1.58 (m, 1H), 1.56-1.41 (m, 5H).

Example 299 4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoicacid (compound 1338)

General procedure J was followed using4-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoic acid ethylester (compound 1336). ¹H NMR (500 MHz, DMSO) δ 8.31 (d 1H), 8.23 (s,1H), 7.94 (d, 1H), 7.85-7.79 (m, 3H), 7.77 (d, 1H), 7.58-7.50 (m, 3H),7.26 (d, 2H), 4.81 (q, 1H), 3.35-3.23 (m, 2H), 2.13-2.05 (m, 1H),1.97-1.89 (m, 2H), 1.76-1.63 (m, 2H), 1.52-1.42 (m, 4H).

Example 3003-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoylamino}-propionicacid methyl ester (compound 1339)

To a solution of4-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoic acid (compound1338) (100 mg) in DMF (1 mL) was added CDI (53 mg) and DIPEA (33 mg).After stirring the solution at r.t. for 4.5 h, β-alanine methyl esterhydrochloride (105 mg) was added. The mixture was stirred overnight,filtered and purified by preparative HPLC-MS (re-analysed by LC/MSmethod A). ¹H NMR (300 MHz, DMSO) δ 8.41 (t, 1H), 8.30 (d, 1H),7.95-7.87 (m, 1H), 7.81-7.64 (m, 4H), 7.57-7.45 (m, 3H), 7.21 (d, 2H),4.65 (q, 1H), 3.59 (s, 3H), 3.46 (dd, 2H), 3.32-3.11 (m, 2H), 2.57 (t,2H), 2.28 (br s, 1H), 2.15-2.01 (m, 1H), 1.98-1.77 (m, 2H), 1.70-1.41(m, 3H), 1.38 (d, 3H).

Example 3011-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoyl}-piperidine-4-carboxylicacid hydrochloride (compound 1340)

A solution of 4-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoicacid (compound 1338) (104 mg, 0.29 mmol), CDI (56 mg, 0.35 mmol) andDIPEA (50 μl, 0.29 mmol) in dry DMF (2 mL) was stirred at r.t.overnight. Piperidine-4-carboxylic acid ethyl ester (168 mg, 0.87 mmol)was added, and the resulting suspension was stirred at r.t. for 3 days.The reaction mixture was filtered, resuspended in DMSO and purified bypreparative HPLC.

The intermediate ethyl ester was hydrolyzed to the title compoundfollowing general procedure J. ¹³C NMR (151 MHz, DMSO) δ 175.38, 168.84,145.41, 133.95, 133.83, 133.33, 130.15, 128.90, 128.86, 126.96, 126.83,126.78, 126.10, 125.54, 124.70, 122.35, 55.41, 50.32, 46.38, 42.61,39.99, 36.66, 32.97, 29.96, 28.14, 20.50.

Example 3023-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoylamino}-propionicacid hydrochloride (compound 1341)

General procedure J was followed using3-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoylamino}-propionicacid methyl ester (compound 1339). ¹H NMR (600 MHz, DMSO) δ 10.08 (br s,2H), 8.48 (t, 1H), 8.33 (d, 1H), 8.05 (d, 1H), 8.01 (d, 1H), 7.96 (d,1H), 7.74 (d, 2H), 7.60 (dt, 3H), 7.25 (d, 2H), 5.28-5.18 (m, 1H),3.50-3.35 (m, 4H), 2.53-2.48 (m, 2H), 2.28-2.19 (m, 1H), 2.11-2.04 (m,1H), 2.00-1.86 (m, 3H), 1.69 (d, 3H), 1.52-1.43 (m, 1H).

Preparation 13: 4-((1S,4S)-4-Acetoxy-cyclopent-2-enyloxy)-benzoic acidmethyl ester

4-hydroxy-benzoic acid methyl ester (6 mmol),(1R,4S)-cis-4-acetoxy-2-cyclopenten-1-ol (4 mmol), and triphenylphosphine (4.8 mmol) were placed in a flask under argon. Dry THF (15 ml)was added through a septum and the resulting solution cooled to 0° C.DIAD was added dropwise, neat, over a period of 20 min. The reactionmixture was left over night. THF was removed in vacuo and the residuewas taken up in MTBE, 10 ml, and diluted to double volume with PE. Afterstanding for 2 hours in the cold, a precipitate of triphenylphosphineoxide was removed on a filter. The filtrate was concentrated in vacuoand purified by chromatography in a gradient from 0 to 20% EtOAc inHeptane.

Preparation 14: 4-((1S,4S)-4-Hydroxy-cyclopent-2-enyloxy)-benzoic acidmethyl ester

4-(4-Acetoxy-cyclopent-2-enyloxy)-benzoic acid methyl ester (preparation13) (3 mmol) and potassium carbonate (3 mmol) were placed in a flaskunder argon. Dry methanol (15 ml) was added, and the resultingsuspension heated at reflux for 1 hour, when TLC indicated completeconversion of substrate. The reaction mixture was concentrated in vacuoand purified by chromatography in a gradient from 0 to 90% EtOAc inHeptane. ¹³C NMR (75 MHz, CDCl3) δ 166.86, 161.87, 139.76, 133.01,131.68, 122.64, 114.79, 81.73, 76.01, 51.88, 41.04.

Preparation 15: 4-((1S,4R)-4-Chloro-cyclopent-2-enyloxy)-benzoic acidmethyl ester

4-(4-Hydroxy-cyclopent-2-enyloxy)-benzoic acid methyl ester (preparation14) (2 mmol), tosyl chloride (2.5 mmol) and DMAP (200 μmol) were placedin a vial. DCM (1 ml) was added through a septum followed by Triethylamine (250 μmol). The reaction mixture was left at r.t. over night. Thereaction mixture was concentrated in vacuo and purified bychromatography in a gradient from 0 to 60% EtOAc in Heptane. ¹³C NMR (75MHz, CDCl3) δ 166.75, 161.50, 137.52, 132.48, 131.70, 122.95, 114.87,80.52, 59.82, 51.89, 41.61.

Preparation 16:4-[(1S,4S)-4-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopent-2-enyloxy]-benzoicacid methyl ester

4-(4-chloro-cyclopent-2-enyloxy)-benzoic acid methyl ester (preparation15) (630 μmol), (+)-(R)-1-naphthalen-1-yl-ethylamine (630 μmol), andpotassium carbonate (630 μmol) were placed in a vial. Dry DMF (1 ml) wasadded, and the resulting suspension heated at 50° C. for 72 hours. Thereaction mixture was diluted with water (25 ml) and extracted twice withethyl acetate. The extract was dried, concentrated in vacuo and purifiedby chromatography in a gradient from 0 to 40% EtOAc in heptane. ¹³C NMR(75 MHz, CDCl3) δ 166.82, 161.93, 140.94, 134.00, 131.64, 131.57,131.24, 130.32, 129.03, 127.38, 125.86, 125.67, 125.37, 123.23, 122.79,122.35, 114.76, 81.98, 61.10, 52.01, 51.79, 39.23, 24.10.

Example 3034-[(1R,3R)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyloxy]-benzoicacid methyl ester (compound 1342)

4-[4-(1-Naphthalen-1-yl-ethylamino)-cyclopent-2-enyloxy]-benzoic acidmethyl ester (preparation 16) was diluted to 0.05 M in iso-propanol.This solution was passed through an H-Cube hydrogenation apparatus at 1atm. hydrogen pressure and a flow rate of 1 ml/min. over 10% Pd oncarbon. The product was concentrated and purified by chromatography in agradient from 0 to 40% EtOAc in Heptane. ¹³C NMR (75 MHz, CDCl3) δ166.91, 161.78, 141.58, 133.99, 131.57, 131.50, 131.23, 129.00, 127.22,125.81, 125.63, 125.35, 122.85, 122.79, 122.15, 114.92, 78.33, 56.02,52.09, 51.78, 40.71, 31.86, 31.06, 24.03.

Example 3044-[(1R,3R)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyloxy]-benzoicacid formiate (compound 1343)

General procedure J was followed using4-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyloxy]-benzoic acid methylester (compound 1342). ¹³C NMR (75 MHz, DMSO) δ 167.01, 163.75, 160.88,140.56, 133.38, 131.14, 130.68, 128.63, 126.96, 125.87, 125.52, 125.34,123.19, 122.97, 122.81, 114.79, 77.87, 55.23, 51.22, 38.71, 30.41,30.36, 23.33.

Preparation 17:3-((1S,4S)-4-Acetoxy-cyclopent-2-enyl)-5-methyl-3H-imidazole-4-carboxylicacid ethyl ester

5-Methyl-1H-imidazole-4-carboxylic acid ethyl ester (6 mmol),(1R,4S)-cis-4-acetoxy-2-cyclopenten-1-ol (4 mmol), and triphenylphosphine (4.8 mmol) were placed in a flask under argon. Dry THF (15 ml)was added through a septum and the resulting solution cooled to 0° C.DIAD was added dropwise, neat, over a period of 20 min. The reactionmixture was left over night. THF was removed in vacuo and the residuewas taken up in MTBE, 10 ml, and diluted to double volume with PE. Afterstanding for 2 hours in the cold, a precipitate of triphenylphosphineoxide was removed on a filter. The filtrate was concentrated in vacuoand purified by chromatography in a gradient from 0 to 20% EtOAc inHeptane. ¹H NMR (300 MHz, CDCl₃) δ7.43 (s, 1H), 6.28 (m, 1H), 6.17 (m,2H), 5.83 (m, 1H), 4.34 (q, 2H), 2.58 (ddd, 1H), 2.49 (s, 3H), 2.16(ddd, 1H), 2.05 (s, 3H), 1.39 (t, 3H).

Preparation 18:3-((1S,4S)-4-Hydroxy-cyclopent-2-enyl)-5-methyl-3H-imidazole-4-carboxylicacid ethyl ester

3-(4-Acetoxy-cyclopent-2-enyl)-5-methyl-3H-imidazole-4-carboxylic acidethyl ester (preparation 17) (3 mmol) and potassium carbonate (3 mmol)were placed in a flask under argon. Dry methanol (15 ml) was added, andthe resulting suspension heated at reflux for 1 hour, when TLC indicatedcomplete conversion of substrate. The reaction mixture was concentratedin vacuo and purified by chromatography in a gradient from 0 to 90%EtOAc in Heptane. ¹H NMR (300 MHz, CDCl₃) δ7.41 (s, 1H), 6.28 (m, 1H),6.12 (m, 1H), 6.04 (m, 1H), 5.08 (m, 1H), 4.34 (q, 2H), 3.62 (bs, 1H),2.47 (s, 3H), 2.42 (m, 1H)m, 2.14 (m, 1H), 1.39 (t, 3H).

Preparation 19:3-((1S,4R)-4-Chloro-cyclopent-2-enyl)-5-methyl-3H-imidazole-4-carboxylicacid ethyl ester

3-(4-Acetoxy-cyclopent-2-enyl)-5-methyl-3H-imidazole-4-carboxylic acidethyl ester (preparation 18) (2 mmol), tosyl chloride (2.5 mmol) andDMAP (200 μmol) were placed in a vial. DCM (1 ml) was added through aseptum followed by triethyl amine (250 μmol). The reaction mixture wasleft at r.t. over night. The reaction mixture was concentrated in vacuoand purified by chromatography in a gradient from 0 to 60% EtOAc inheptane. ¹H NMR (300 MHz, CDCl₃) δ7.61 (s, 1H), 6.29 (m, 1H), 6.09 (m,1H), 6.01 (m, 1H), 4.95 (m, 1H), 4.34 (q, 2H), 3.20 (m, 1H), 2.48 (s,3H), 2.15 (m, 1H), 1.38 (t, 3H).

Preparation 20:5-Methyl-3-[(1S,45)-4-((R)-1-naphthalen-1-yl-ethylamino)-cyclopent-2-enyl]-3H-imidazole-4-carboxylicacid ethyl ester

3-(4-Chloro-cyclopent-2-enyl)-5-methyl-3H-imidazole-4-carboxylic acidethyl ester (preparation 19) (630 μmol),(+)-(R)-1-naphthalen-1-yl-ethylamine (630 μmol), and potassium carbonate(630 μmol) were placed in a vial. Dry DMF (1 ml) was added, and theresulting suspension heated at 50° C. for 72 hours. The reaction mixturewas diluted with water (25 ml) and extracted twice with ethyl acetate.The extract was dried, concentrated in vacuo and purified bychromatography in a gradient from 0 to 40% EtOAc in heptane. ¹H NMR (300MHz, CDCl₃) δ8.19 (d, 1H) 7.85 (d, 1H), 7.71 (m, 2H), 7.47 (m, 3H), 7.30(s, 1H), 6.16 (m, 1H), 6.04 (m, 1H), 5.88 (m, 1H), 4.74 (q, 1H), 4.33(q, 2H), 3.94 (m, 1H), 2.45 (s, 3H), 2.35 (m, 1H), 2.05 (m, 1H), 1.48(d, 3H), 1.38 (t, 3H).

Example 3055-Methyl-3-[(1R,3R)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-3H-imidazole-4-carboxylicacid (compound 1344)

Step 1

5-Methyl-3-[4-(1-naphthalen-1-yl-ethylamino)-cyclopent-2-enyl]-3H-imidazole-4-carboxylicacid ethyl ester (preparation 20) was diluted to 0.05 M in iso-propanol.This solution was passed through an H-Cube hydrogenation apparatus at 1atm. hydrogen pressure and a flow rate of 1 ml/min. over 10% Pd oncarbon. The product was concentrated and purified by chromatography in agradient from 0 to 40% EtOAc in Heptane, affording5-methyl-3-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-3H-imidazole-4-carboxylicacid ethyl ester.

Step 2

General procedure J was followed using5-methyl-3-[3-(1-naphthalen-1-yl-ethylamino)-cyclopentyl]-3H-imidazole-4-carboxylicacid ethyl ester. ¹H NMR (300 MHz, DMSO) δ 8.27 (m, 1H), 7.95 (m, 1H),7.86 (m, 1H), 7.78 (m, 1H), 7.71 (m, 1H), 7.54 (m, 3H), 5.43 (m, 1H),4.87 (m, 1H), 3.37 (m, 1H), 2.31 (s, 3H), 2.20 (m, 2H), 2.05-1.55 (m,4H), 1.49 (d, 3H).

Example 306(3S,4S-Diphenyl-cyclopentyl)-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1345)

General procedure A was followed using 3S,4S-diphenyl-cyclopentanone and(+)-(R)-1-naphthalen-1-yl-ethylamine. ¹H NMR (300 MHz, CDCl3) δ 8.19 (d,1H), 7.91-7.84 (m, 1H), 7.76 (d, 1H), 7.72-7.64 (m, 1H), 7.55-7.42 (m,3H), 7.23-6.97 (m, 10H), 4.84-4.73 (m, 1H), 3.48-3.28 (m, 2H), 3.05-2.92(m, 1H), 2.52-2.38 (m, 1H), 2.17-2.00 (m, 2H), 1.89-1.70 (m, 1H), 1.54(d, 3H).

Example 3075-(4-ethoxy-phenyl)-2-propyl-cyclohexyl]-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1346)

A solution of 3-(4-ethoxy-phenyl)-6-propyl-cyclohex-2-enone (100 mg) inisopropanol (8 mL) was hydrogenated in an H-CUBE (Catalyst: Pd/C, Flow:1 ml/min, H₂ pressure: 1 bar and loop size: 5 ml). The conjugateddoublebond was hydrogenated in 2 runs (˜80% conversion). Evaporation ofthe isopropanol resulted in a colourless oil, which was dissolved inacetonitrile (3 ml). (R)-1-Naphthalen-1-yl-ethylamine and NaBH(OAc)₃were added and the reaction was stirred over night at room temperature.The reaction mixture was extracted with EtOAc/NaHCO₃ aq. The organicphase was dried (MgSO₄) and evaporated after filtration. The oil wasdissolved in methanol and purified by preparative HPLC-MS. LC/MS (methodB): RT=3.72, [M+H]⁺=416.6.

Example 308[2-(4-Fluoro-phenyl)-5-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-aceticacid hydrochloride (compound 1347)

A mixture of [2-(4-fluoro-phenyl)-5-oxo-cyclopent-1-enyl]-acetic acidand 10% Pd/C in methanol was left under an H₂-atmosphere for 3 days. Thereaction mixture was filtered through Celite and evaporated to an oil.The oil was dissolved in acetonitrile. (R)-1-Naphthalen-1-yl-ethylamineand NaBH(OAc)₃ were added and the reaction was stirred over night atroom temperature. The reaction mixture was extracted with EtOAc/NaHCO₃aq. The organic phase was isolated, dried (MgSO₄) and evaporated afterfiltration. The oil was dissolved in methanol and purified bypreparative HPLC-MS resulting in the desired product. The desiredproduct was dissolved in acetonitrile. HCl in dioxane (1 eq) was addedand the HCl salt of the product (title compound) precipitated and wascollected by filtration. ¹H NMR (300 MHz, DMSO) δ 12.37 (br s, 1H), 9.71(br s, 2H), 8.28 (d, 1H), 8.09-7.96 (m, 3H), 7.69-7.56 (m, 3H),7.38-7.28 (m, 2H), 7.12 (t, 2H), 5.43-5.29 (m, 1H), 3.87-3.73 (m, 1H),2.86-2.71 (m, 1H), 2.58-2.45 (m, 1H), 2.44-2.36 (m, 2H), 2.14-1.83 (m,4H), 1.75 (d, 3H).

Example 3093-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propan-1-ol(compound 1348)

To a solution of3-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid methyl ester (compound 1183) (215 mg, 0.54 mmol) in dry diethylether (3 mL) was added LiAlH₄ (0.62 mL of a 1M solution in THF) at 0° C.After 30 min, the reaction was quenched with water and purified bypreparative HPLC to afford the title compound as an oil. ¹H NMR (300MHz, DMSO) δ 8.30 (d, 1H), 7.95-7.87 (m, 1H), 7.80-7.68 (m, 2H),7.57-7.44 (m, 3H), 7.03 (s, 4H), 4.64 (q, 1H), 4.42 (t, 1H), 3.46-3.29(m, 2H), 3.24-3.08 (m, 2H), 2.59-2.47 (m, 2H), 2.35-1.30 (m, 11H).

Example 310 Functional Whole Cell Assay

On the assay day cells were harvested and resuspended to 13*10⁶ cells/mlin stimulation buffer (containing: Hepes 10 mM, MgCl₂ 0.5 mM, KCl 4.2mM, NaCl 146 mM, glucose 5.5 mM, LiCl 50 mM at pH 7.4). Five μl cellsolution were pipetted into a well (white 384-well plate, Perkin ElmerOptiplate) followed by 5 μl compound diluted in a Ca²⁺-containing (tothe final concentration of 2 mM) buffer. After compound stimulation for1 hour at 37° C. 10 ul of IP-One assay reagents were added and incubatedfor another 1 hour at room temperature. Finally the plate was read usinga Perkin Elmer EnVision, according to protocol supplied by the IP-Oneassay kit manufacturer. The FRET ratio was calculated by dividing the665 nm emission signal with that of the 615 nm.

Molar concentrations of a compound that produces 50% of the maximumpossible agonistic response (the IC50 value) is calculated according toequation General sigmoidal curve with Hill slope, a to d (Equation 1)This model describes a sigmoidal curve with an adjustable baseline, a.The equation can be used to fit curves where response is eitherincreasing or decreasing with respect to the independent variable, X.

y=(a−d)/(1+(x/c)̂b)+d  Equation 1

Parameters:

x=concentration of tested compoundy=response (%)a=min response as compound concentration approaches 0d=max response as concentration of tested compound increasingc=IC50 for the curveb=Hill coefficient or curve slope

Testing data of compounds of the present invention indicate thatcompounds of the present invention are potent modulators of CaSR, thusmaking them potentially useful in the treatment of diseases related tokidneys or bones. See table 1 below.

TABLE 1 In vitro testing of compounds in CaSR functional whole cellassay Compound IC50 (nM) Cinacalcet 630 Compound 1056 250 Compound 111550 Compound 1136 40 Compound 1142 50 Compound 1146 50 Compound 1186 40Compound 1188 20 Compound 1190 8 Compound 1338 16

Example 311 Screening for P450 2D6 Inhibition

The assay rapidly screen for potential inhibitors of human P450 2D6catalytic activity, by using recombinant human P450 2D6. The IC50determination is performed in duplicate at eight concentrations.

Incubations were conducted in 96 well microtiter plates based on amethod described by BD Biosciences. To the first well in each row, aNADPH regenerating system and test compound was added. In the secondwell and all remaining wells, NADPH regenerating system and acetonitrile(final concentration of 2%) was added. The final assay concentration ofthe NADPH regenerating system was 8.2 μM NADP⁺, 0.41 mMglucose-6-phosphate, 0.41 mM magnesium chloride hexahydrate and 0.4 U/mlglucose-6-phosphate dehydrogenase and 0.01 mg/mL control insect cellmembrane protein. The test compound solution was serially diluted 1:3through the eighth wells.

The final concentration of the test compounds were in the range 100 μMto 45.7 nM in the eight rows. Wells 9 and 10 contained no test compound(only NADPH regenerating system and enzyme/substrate mix) and wells 11and 12 were used as controls for background fluorescence (enzyme andsubstrate were added after the reaction was terminated). The plate wasthen pre-incubated at 37° C. for 10 min, and the reaction was initiatedby the addition of pre-warmed enzyme/substrate mix. The assayconcentration of the enzyme/substrate mix was 100 mM potassiumphosphate, pH 7.4, 1.5 pmol recombinant human P450 CYP2D6 and 1.5 μM ofthe fluorescent substrate 3-[2-(N,Ndiethyl-N-methylamino)ethyl]-7-methoxy-4-methylcounnarin (AMMC). Theassay was conducted in duplicate in a final volume of 200 μL per well.Reactions were terminated after 30 min by addition of a 4:1,acetonitrile:0.5 M Tris base solution. Quinidine was used as positivecontrol, 0.5 μM as highest concentration. Fluorescence per well wasmeasured using a fluorescence plate reader (excitation: 390 nm,emission: 460 nm). The IC50 values were calculated.

Testing data of compounds of the present invention indicate thatcompounds of the present invention show low or no inhibition towardshuman P450 2D6 (pIC50-value below 6). See table 2 below.

TABLE 2 In vitro testing of compounds in CYP 2D6 and CYP 3A4 inhibitionassay. Compound IC50 (μM) Cinacalcet 0.050 Compound 1186 50 Compound1190 79 Compound 1338 100 Compound 1146 16 Compound 1142 25 Compound1136 10 Compound 1115 13 Compound 1056 10

Example 312 Profiling of a Compound According to the Present Inventionon Off-Target, G-Protein Coupled Receptors

A compound according to the present invention along with Cinacalcet wassent to CEREP for functional testing on cell membrane receptors. Allexperiments were carried out on human receptors which were expressed inmammalian cells. EC₅₀ (agonism) and IC₅₀ (antagonism) were calculated ona 6 point curve with concentrations ranging from 0.01-100 mM.

The results of the functional cell-based screening showed that thecompound according to the present invention was significantly lesspotent on the opiate (MOP) receptor, serotonin 5-HT1A receptor andnorepinephrine uptake transporter compared to Cinacalcet.

Example 313 Profiling of Compounds of the Present Invention onCardiac-Related, In Vitro Ion Channels

Compounds of the present invention were in vitro tested on three cardiacion channels that are responsible for three major components of thecardiac action potential. These channels are:

-   -   1. Cloned hERG potassium channels (encoded by the KCNH2 gene and        expressed in human embryonic kidney, HEK293, cells), responsible        for I_(Kr)    -   2. Cloned hNav1.5 sodium channel (encoded by the human SCN5A        gene and expressed in HEK293 cells), responsible for I_(Na),        fast sodium current    -   3. Cloned L-type calcium channels (hCav1.2, encoded by the human        CACNA1C gene in CHO cells), responsible for I_(Ca,L), high        threshold calcium current.

The effect of a compound according to the present invention wasevaluated at the ChanTest Corporation, Ion Channel Company in Cleveland,Ohio, USA. The compound was tested at room temperature using thePatchXpress 7000A (Molecular Devices) on the channels listed above andevaluated at 0.01, 0.1, 1, 10, and 100 μM with each concentration testedin 2-6 cells (n≧2) for 5 min. The effect the compound on hNav1.5 wasdetermined using 5 Hz repetitive stimulation for 5 min.

The IC₅₀ values for the tested compound were >100 μM in the hERG andhCav1.2 channel assays. No use dependent inhibition was observed atconcentrations up to 100 μM on the hNav1.5 channel. The results of thepositive controls (E-4031 for hERG, Lidocaine for hNav1.5, andNifedipine for hCav1.2) confirmed the sensitivity of the test system. Insummary, no significant activity was detected on the three cardiac ionchannels that are responsible for three major components of the cardiacaction potential.

Example 314 In Vivo Test in Normal Rats

Various compounds were administered to normal male Sprague Dawley ratsin order to examine the pharmacological effect on serum levels of totalcalcium and parathyroid hormone (PTH). The experiments were performed byorally administering a single dose of the respective compounds ascompared to vehicle-treated animals or animals treated with thecompetitor compound Cinacalcet.

As a standard, a group of six animals were treated orally with 1 mg/kgof compound as a 1% methylcellulose suspension and two hours thereafter,blood was obtained by retro-orbital bleeding under anaesthesia and theserum calcium and PTH levels were measured. Percent PTH and calciumsuppression, respectively, compared to vehicle-treated animals is shownin table 3.

In some instances, rats were treated orally with various doses of agiven compound in 1% methylcellulose (six rats/dose) and blood wasobtained by retro-orbital bleeding two hours thereafter. Thedose-response curve for suppression of serum PTH and serum calciumlevels by the indicated compounds are shown in FIG. 1-FIG. 4. Using thesoftware GraphPad Prism® 5, ED₅₀ values for Cinacalcet, Compound 1056,Compound 1186, and Compound 1190 with respect to PTH suppression werecalculated to be 0.9 mg/kg, 0.1 mg/kg, 0.04 mg/kg, and 0.002 mg/kg,respectively.

For some compounds, rats were bled at several time-points after oraladministration (six rats/time point), and suppression of serum PTHlevels was observed over time. Results are shown in FIGS. 5-8.

TABLE 3 Percent PTH and calcium suppression, respectively, of compoundsin this invention compared to vehicle-treated animals. PTH Suppressionof Compound Dose p.o. suppression Ca²⁺ Cinacalcet 1 mg/kg 48% 5%Compound 1056 1 mg/kg 85% 1% Compound 1115 1 mg/kg 50% 3% Compound 11361 mg/kg 61% 7% Compound 1146 1 mg/kg 84% 0% Compound 1186 1 mg/kg 98% 6%Compound 1188 1 mg/kg 97% 12%  Compound 1190 1 mg/kg 93% 18.5%  Compound 1338 1 mg/kg 85% 29% 

Example 315 In Vivo Test Using the 5/6 Nephrectomy Model in Rats

The lowering effect of different compounds on serum PTH was examined invivo in the rat 5/6 nephrectomy model which is a widely accepted animalmodel of secondary hyperparathyroidism.

Two-third of the rats' (Sprague Dawley, at least 8 weeks old) leftkidney was surgically removed followed by removal of the right kidneyone week later. Immediately after this procedure, the rodent diet wasswitched from a standard diet (Altromin, 0.9% Ca2+, 0.7% Pi) to ahigh-phosphorus diet (Altromin, 0.9% Ca2+, 1.2% Pi) and animals wereobserved for 3 weeks, in which they developed severe secondaryhyperparathyroidism.

After disease initiation, blood was obtained by retro-orbital bleedingand urine was collected using metabolic cages. Serum PTH, calcium,phosphorus, albumin, creatinine, and BUN as well as urinary creatinineand albumin were measured. Rats were then stratified into differenttreatment groups (9-12 rats/group) based on the results obtained. Onegroup of normal rats without surgery served as control (“control”) andone group of nephrectomized rats treated with vehicle (1%Methylcellulose) was used as another control (“5/6 NEPX”). All othergroups were treated orally with test compound at various doses oncedaily for two weeks and the above mentioned parameters were monitoredweekly.

As shown in FIG. 9, the PTH lowering effect the test compounds wasconfirmed. The calculated ED₅₀ values for Cinacalcet, compound 1056,compound 1186, and compound 1190 were approx. 20 mg/kg, 2 mg/kg, 0.3mg/kg, and 0.01 mg/kg, respectively.

1. A compound of general formula I

wherein

represents cycloalkyl comprising 4-7 carbon atoms optionally beingsubstituted with one or more, same of different substitutents selectedfrom R₂, R₃, R₄ or R₅; A represents C₁₋₁₀heteroaryl, C₆₋₁₄aryl orC₆₋₁₀heterocycloalkylaryl, each of which are optionally substituted withone or more, same or different substituents represented by halogen,hydroxy, mercapto, trifluoromethyl, cyano, carboxy, —NH₂, —C(O)NH₂,nitro, oxo, —S(O)₂NH₂, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄hydroxyalkyl,C₁₋₆haloalkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkylcarbonyloxy,C₁₋₄alkoxycarbonyloxy, C₁₋₄alkoxysulfonyloxy, C₁₋₄alkoxycarbamoyl,C₁₋₄aminocarbonyl, C₁₋₄alkylthio, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,C₁₋₆amino, iminomethyl, C₁₋₄aminosulfonyl, C₁₋₄aminocarbonyloxy,C₁₋₄alkylsulfonylamino, hydroxyiminomethyl, C₁₋₄alkylcarbonylamino,C₁₋₄alkylsulfonyl, C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl,C₁₋₁₀heteroaryl or C₆₋₁₄aryl, wherein said C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, C₁₋₄hydroxyalkyl, C₁₋₆haloalkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy,C₁₋₄alkoxysulfonyloxy, C₁₋₄alkoxycarbamoyl, C₁₋₄aminocarbonyl,C₁₋₄alkylthio, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, C₁₋₆amino, iminomethyl,C₁₋₄aminosulfonyl, C₁₋₄aminocarbonyloxy, C₁₋₄alkylsulfonylamino,hydroxyiminomethyl, C₁₋₄alkylcarbonylamino, C₁₋₄alkylsulfonyl,C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl, C₁₋₁₀heteroaryl orC₆₋₁₄aryl, are optionally further substituted with one or more, same ordifferent substituents selected from halogen, hydroxy, —NH₂, mercapto,trifluoromethyl, cyano, carboxy, —C(O)NH₂, nitro, oxo, —S(O)₂NH₂,C₁₋₄alkyl, C₁₋₆haloalkyl, C₁₋₃alkoxy or C₁₋₃hydroxyalkyl; R₁ isC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆hydroxyalkyl, C₁₋₆haloalkyl,C₁₋₆alkylamino, C₃₋₆cycloalkyl, or C₁₋₆heterocycloalkyl, each of whichare optionally substituted with one or more, same or differentsubstituents selected from halogen, hydroxy, mercapto, trifluoromethyl,cyano, carboxy, NH₂, —C(O)NH₂, nitro, oxo, C₁₋₃alkyl, C₂₋₄alkenyl,C₁₋₃hydroxyalkyl, C₁₋₃haloalkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl orC₁₋₄amino; R₂ and R₃ independently of each other represent hydrogen,cyano, halogen, carboxy, —C(O)NH₂, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆hydroxyalkyl, C₁₋₆haloalkyl, aminoC₁₋₆alkyl, C₃₋₆cycloalkyl,C₁₋₆heterocycloalkyl, C₁₋₆alkoxy, C₁₋₆aminocarbonyl,C₆₋₁₀aryloxycarbonyl, C₁₋₆amino, C₆₋₁₀arylamino,C₁₋₄alkoxycarbonylamino, C₁₋₄alkylcarbonylamino,C₂₋₄alkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino orC₁₋₆heterocycloalkylcarbonylamino, wherein said —C(O)NH₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆hydroxyalkyl, C₁₋₆haloalkyl,aminoC₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆heterocycloalkyl, C₁₋₄alkoxy,C₁₋₆aminocarbonyl, C₆₋₁₀aryloxycarbonyl, C₁₋₆amino, C₆₋₁₀arylamino,C₁₋₄alkoxycarbonylamino, C₁₋₄alkylcarbonylamino,C₂₋₄alkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino orC₁₋₆heterocycloalkylcarbonylamino, are optionally substituted with oneor more, same or different substituents represented by halogen, hydroxy,mercapto, trifluoromethyl, cyano, carboxy, —NH₂, —C(O)NH₂, nitro,C₁₋₃alkyl, C₂₋₄alkenyl, C₁₋₃hydroxyalkyl, C₁₋₃haloalkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl or C₁₋₄amino; R₄ represents hydrogen, halogen,hydroxy, carboxy, —NH₂, —C(O)NH₂, C₁₋₆alkyl, C₂₋₆alkynyl, C₂₋₆alkynyl,C₁₋₆hydroxyalkyl, C₁₋₆haloalkyl, aminoC₁₋₆alkyl, C₃₋₆cycloalkyl,C₁₋₆heterocycloalkyl, C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, C₁₋₆aminocarbonyl,C₆₋₁₀aryloxycarbonyl, C₁₋₁₀heteroaryloxycarbonyl, C₁₋₆amino,C₆₋₁₀arylamino, C₁₋₁₀heteroarylamino, C₆₋₁₀arylC₁₋₆amino,C₁₋₄alkoxycarbonylamino, C₁₋₄alkylcarbonylamino,C₂₋₄alkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino orC₁₋₆heterocycloalkylcarbonylamino, wherein said —C(O)NH₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆hydroxyalkyl, C₁₋₆haloalkyl,aminoC₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆heterocycloalkyl, C₁₋₆alkoxy,C₁₋₆alkoxycarbonyl, C₁₋₆aminocarbonyl, C₆₋₁₀aryloxycarbonyl,C₁₋₁₀heteroaryloxycarbonyl, C₁₋₆amino, C₆₋₁₀arylamino,C₁₋₁₀heteroarylamino, C₆₋₁₀arylC₁₋₆amino, C₁₋₄alkoxycarbonylamino,C₁₋₄alkylcarbonylamino, C₂₋₄alkenylcarbonylamino,C₃₋₆cycloalkylcarbonylamino or C₁₋₆heterocycloalkylcarbonylamino, areoptionally substituted with one or more, same or different substituentsrepresented by halogen, hydroxy, mercapto, trifluoromethyl, cyano,carboxy, —NH₂, hydroxyiminomethyl, —C(O)NH₂, nitro, C₁₋₃alkyl,C₂₋₄alkenyl, C₁₋₃hydroxyalkyl, C₁₋₃haloalkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl or C₁₋₄amino; each of R₅ represents independently oneor more same or different substituents represented by hydrogen, halogen,hydroxy, carboxy, —NH₂, —C(O)NH₂, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆hydroxyalkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, C₁₋₆heterocycloalkyl,C₁₋₆alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₆aminocarbonyl, C₆₋₁₀aryloxycarbonyl,C₁₋₁₀heteroaryloxycarbonyl, C₁₋₆amino, C₆₋₁₀aryl, C₆₋₁₀arylamino,C₁₋₁₀heteroarylamino, C₆₋₁₀arylcarbonylamino, C₁₋₄alkoxycarbonylamino,C₆₋₁₀arylsulfonylamino, C₁₋₄alkylcarbonylamino,C₂₋₄alkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino orC₁₋₆heterocycloalkylcarbonylamino, wherein said C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆hydroxyalkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl,C₁₋₆heterocycloalkyl, C₁₋₆alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₆aminocarbonyl,C₆₋₁₀aryloxycarbonyl, C₁₋₁₀heteroaryloxycarbonyl, C₁₋₆amino, C₆₋₁₀aryl,C₆₋₁₀arylamino, C₁₋₁₀heteroarylamino, C₆₋₁₀arylcarbonylamino,C₁₋₄alkoxycarbonylamino, C₆₋₁₀arylsulfonylamino, C₁₋₄alkylcarbonylamino,C₂₋₄alkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino orC₁₋₆heterocycloalkylcarbonylamino, are optionally further substitutedwith one or more, same or different substituents selected from halogen,hydroxy, mercapto, cyano, trifluoromethyl, carboxy, —NH₂, —C(O)NH₂,nitro, oxo, C₁₋₃alkyl, C₂₋₄alkenyl, C₁₋₃hydroxyalkyl, C₁₋₃haloalkyl,C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, iminomethyl or hydroxyiminomethyl; Grepresents hydrogen, —C(O)H, —C(O)NH₂, —O—C(O)NH₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆hydroxyalkyl, C₁₋₆haloalkyl, C₁₋₆amino,C₃₋₈cycloalkyl, C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl,C₃₋₈cycloalkenyl, C₆₋₁₄aryl, C₁₋₁₀heteroaryl, C₆₋₁₀arylamino,hydroxyaminocarbonyl, C₆₋₁₀arylaminocarbonyl, C₁₋₄aminocarbonyl,C₁₋₆heterocycloalkylcarbonyl, C₁₋₁₀heteroarylaminocarbonyl,C₆₋₁₀arylsulfonylaminocarbonyl, C₆₋₁₄aryloxy, C₁₋₁₀heteroaryloxy,C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkylcarbonyloxy,C₁₋₄alkoxycarbonyloxy, C₁₋₆aminocarbonyloxy, C₁₋₁₀heteroarylamino,C₁₋₃alkylcarbonylamino, C₆₋₁₀arylcarbonylamino,C₃₋₆cycloalkylcarbonylamino, C₁₋₄alkoxycarbonylamino,C₁₋₆heterocycloalkylcarbonylamino or ureido, wherein said —C(O)H,—C(O)NH₂, —O—C(O)NH₂, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆hydroxyalkyl, C₁₋₆haloalkyl, C₁₋₆amino, C₃₋₈cycloalkyl,C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl, C₃₋₈cycloalkenyl,C₆₋₁₄aryl, C₁₋₁₀heteroaryl, C₆₋₁₀arylamino, hydroxyaminocarbonyl,C₆₋₁₀arylaminocarbonyl, C₁₋₄aminocarbonyl, C₁₋₆heterocycloalkylcarbonyl,C₁₋₁₀heteroarylaminocarbonyl, C₆₋₁₀arylsulfonylaminocarbonyl,C₆₋₁₄aryloxy, C₁₋₁₀heteroaryloxy, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy, C₁₋₆aminocarbonyloxy,C₁₋₁₀heteroarylamino, C₁₋₃alkylcarbonylamino, C₆₋₁₀arylcarbonylamino,C₃₋₆cycloalkylcarbonylamino, C₁₋₄alkoxycarbonylamino,C₁₋₆heterocycloalkylcarbonylamino or ureido, are optionally furthersubstituted with one or more, same or different substituents representedby halogen, cyano, carboxy, —NH₂, C₁₋₆amino, iminomethyl,hydroxyiminomethyl, amidino, hydroxy, mercapto, —C(O)H, —C(O)NH₂, nitro,oxo, trifluoromethyl, C₁₋₆alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄hydroxyalkyl, aminoC₁₋₃alkyl, C₁₋₆haloalkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₄alkylcarbonyl, C₁₋₄aminocarbonyl,hydroxyaminocarbonyl, C₃₋₆cycloalkylaminocarbonyl,C₁₋₆heterocycloalkylaminocarbonyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl,C₁₋₆cycloalkylamino, C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl,C₁₋₆heterocycloalkylcarbonyl, C₆₋₁₄aryl, carboxyC₆₋₁₀aryl,C₁₋₆heteroaryl, C₁₋₆heteroarylaminocarbonyl, —S(O)₂NH₂, C₁₋₆ureido,C₁₋₆thioureido, C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy,C₁₋₄alkoxysulfonyloxy, C₁₋₆heterocycloalkyloxy, C₁₋₄alkylthio,C₁₋₄aminosulfonyl, C₁₋₄aminocarbonyloxy, C₁₋₄alkylsulfonylamino,C₆₋₁₀arylamino, C₆₋₁₀arylaminocarbonyl, C₆₋₁₀ aryloxycarbonyl,C₁₋₄alkoxycarbamoyl, C₆₋₁₀arylcarbonylamino, C₆₋₁₀arylsulfonylamino,C₁₋₄alkylcarbonylamino, C₁₋₄alkenylcarbonylamino,C₃₋₆cycloalkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino,C₁₋₄alkoxycarbonylamino, C₁₋₆heterocycloalkylcarbonylamino,C₁₋₄alkylsulfonyl, C₁₋₆heterocycloalkylsulfonyl orC₁₋₃alkylsulfonylaminocarbonyl, wherein said carboxy, C₁₋₆amino,iminomethyl, hydroxyiminomethyl, C(O)NH₂, C₁₋₆alkyl, C₂₋₄alkenyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄hydroxyalkyl, aminoC₁₋₃alkyl,C₁₋₆haloalkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkylcarbonyl,C₁₋₄aminocarbonyl, hydroxyaminocarbonyl, C₃₋₆cycloalkylaminocarbonyl,C₁₋₆heterocycloalkylaminocarbonyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl,C₁₋₆cycloalkylamino, C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkenyl,C₁₋₆heterocycloalkylcarbonyl, C₆₋₁₄aryl, carboxyC₆₋₁₀aryl,C₁₋₆heteroaryl, C₁₋₆heteroarylaminocarbonyl, —S(O)₂NH₂, C₁₋₆ureido,C₁₋₆thioureido, C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy,C₁₋₄alkoxysulfonyloxy, C₁₋₆heterocycloalkyloxy, C₁₋₄alkylthio,C₁₋₄aminosulfonyl, C₁₋₄aminocarbonyloxy, C₁₋₄alkylsulfonylamino,C₆₋₁₀arylamino, C₆₋₁₀arylaminocarbonyl, C₆₋₁₀aryloxycarbonyl,C₁₋₄alkoxycarbamoyl, C₆₋₁₀arylcarbonylamino, C₆₋₁₀arylsulfonylamino,C₁₋₄alkylcarbonylamino, C₁₋₄alkenylcarbonylamino,C₃₋₆cycloalkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino,C₁₋₄alkoxycarbonylamino, C₁₋₆heterocycloalkylcarbonylamino,C₁₋₄alkylsulfonyl, C₁₋₆heterocycloalkylsulfonyl orC₁₋₃alkylsulfonylaminocarbonyl, are optionally further substituted withone or more, same or different substituents selected from hydroxy,—NH_(z) C₁₋₆amino, iminomethyl, hydroxyiminomethyl, carboxy,trifluoromethyl, halogen, oxo, mercapto, cyano, —C(O)NH₂, nitro,C₁₋₆alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄hydroxyalkyl, C₁₋₆haloalkyl,C₁₋₃alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄alkylcarbonyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, C₁₋₆heterocycloalkyl, C₆₋₁₂aryl, C₁₋₁₀heteroaryl,C₁₋₃alkoxyC₆₋₁₀aryl, C₁₋₁₀heterocycloalkylaryl, C₁₋₆heterocycloalkenyl,—S(O)₂NH₂, —S(O)₂OH, —S(O)₂CH₃, C₁₋₆ureido, C₁₋₆thioureido,C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy, C₁₋₄alkoxysulfonyloxy,C₁₋₄alkoxycarbamoyl, C₁₋₄aminocarbonyl, C₁₋₆heterocycloalkylcarbonyl,C₁₋₄alkylthio, C₁₋₄aminosulfonyl, C₁₋₄aminocarbonyloxy,C₁₋₄alkylsulfonylamino, C₆₋₁₄arylsulfonyl, C₆₋₁₀arylsulfonylamino,hydroxyiminomethyl, C₁₋₄alkylcarbonylamino or C₁₋₄alkylsulfonyl, whereinsaid —C(O)NH₂, C₁₋₆amino, C₁₋₆alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄hydroxyalkyl, C₁₋₆haloalkyl, C₁₋₃alkoxy, C₁₋₄alkoxycarbonyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, C₁₋₆heterocycloalkyl, C₆₋₁₂aryl,C₁₋₁₀heteroaryl, C₁₋₃alkoxyC₆₋₁₀aryl, C₁₋₁₀heterocycloalkylaryl,C₁₋₆heterocycloalkenyl, —S(O)₂NH₂, —S(O)₂OH, C₁₋₆ureido, C₁₋₆thioureido,C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy, C₁₋₄alkoxysulfonyloxy,C₁₋₄alkoxycarbamoyl, C₁₋₄aminocarbonyl, C₁₋₆heterocycloalkylcarbonyl,C₁₋₄alkylthio, C₁₋₄aminosulfonyl, C₁₋₄aminocarbonyloxy,C₁₋₄alkylsulfonylamino, C₆₋₁₄arylsulfonyl, C₆₋₁₀arylsulfonylamino,hydroxyiminomethyl, C₁₋₄alkylcarbonylamino or C₁₋₄alkylsulfonyl, areoptionally further substituted with one or more, same or differentsubstituents selected from hydroxy, oxo, cyano, halogen,trifluoromethyl, C₁₋₃alkoxy, C₁₋₃alkoxyC₁₋₃alkoxy, C₁₋₆amino, mercapto,carboxy, —C(O)NH₂, nitro, C₁₋₆alkyl, C₁₋₃hydroxyalkyl,C₁₋₄alkoxycarbonyl, C₁₋₃alkylcarbonylamino, C₁₋₆heterocycloalkyl,C₆₋₁₂aryl, C₁₋₆heteroaryl, —S(O)₂NH₂ or —S(O)₂OH; or G, together withR₄, forms an oxo group; provided that the compound is notN-cyclopentyl-α-methyl-benzenemethanamine,N-cyclohexyl-α-methyl-benzenemethanamine,3-[3-[(1-phenylethyl)amino]cyclohexyl]-phenol,2-[3-[3-[(1-phenylethyl)amino]cyclohexyl]phenoxy]-, ethyl ester, aceticacid,N-[3-(3-methoxyphenyl)cyclohexyl]-α-methyl-2-naphthalenemethanamine,N-[3-(3-methoxyphenyl)cyclohexyl]-α-methyl-benzenemethanamine,N-cyclohexyl-α-methyl-1-naphthalenemethanamine,3-methoxy-α-methyl-N-(2-phenylcyclohexyl)-benzenemethanamine,3-methoxy-α-methyl-N-(3-phenylcyclohexyl)-benzenemethanamine,3-methoxy-α-methyl-N-(4-phenylcyclohexyl)-benzenemethanamine,4-chloro-N-cyclohexyl-α-methyl-benzenemethanamine,N-(1-phenylethyl)-cycloheptanamine,α-[[3-phenyl-4-[[4-[3-phenylpropyl]-1-piperidinyl]methyl]cyclopentyl]amino]-benzeneaceticacid,9-chloro-5-[3-[2-hydroxy-1-phenylethylamino]cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one,(1R,3S,11S)-methyl-cis-N-(1-phenylethyl)-3-amino-cyclopentanecarboxylatehydrochloride,4,4-dimethyl-2-(1-phenyl-ethylamino)-cyclopentanecarboxylic acid methylester,4,4-di(tert-butoxymethyl)-2-(1-phenyl-ethylamino)-cyclopentanecarboxylicacid methyl ester,5-methyl-2,4-diphenyl-6-(1-phenyl-ethylamino)-cyclohexane-1,3-dicarboxylicacid 3-tert-butyl ester,5-methyl-2,4-diphenyl-6-(1-phenyl-ethylamino)-cyclohexane-1,3-dicarboxylicacid di-tert-butyl ester, or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof.
 2. A compound according to claim1 wherein compound I represents


3. A compound according to claim 1 or 2, wherein

represents:


4. A compound according to claim 1, wherein R₂ and R₃ representhydrogen.
 5. A compound according to claim 1, wherein G represents—C(O)—R₆, wherein R₆ represents —NH₂, C₁₋₆amino, hydroxy, mercapto,—C(O)NH₂, trifluoromethyl, carboxy, C₁₋₆alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄hydroxyalkyl, C₁₋₆haloalkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₄aminocarbonyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl,C₁₋₆heterocycloalkenyl, C₃₋₆cycloalkylamino, C₁₋₆heterocycloalkyl,C₁₋₆heterocycloalkylcarbonyl, C₆₋₁₄aryl, C₁₋₆heteroaryl, C₆₋₁₀arylamino,carboxyC₆₋₁₀aryl, C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy,C₁₋₄alkoxysulfonyloxy, C₁₋₄alkylthio, C₁₋₄aminocarbonyloxy,C₁₋₄alkylsulfonylamino, C₁₋₄alkylcarbonylamino,C₁₋₄alkenylcarbonylamino, C₃₋₆cycloalkenylcarbonylamino,C₃₋₆cycloalkylcarbonylamino, C₁₋₄alkoxycarbonylamino,C₆₋₁₀arylcarbonylamino or C₆₋₁₀arylsulfonylamino, wherein saidC₁₋₆amino, C₁₋₆alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄hydroxyalkyl,C₁₋₆haloalkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₄aminocarbonyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, C₁₋₆heterocycloalkenyl,C₃₋₆cycloalkylamino, C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkylcarbonyl,C₆₋₁₄aryl, C₁₋₆heteroaryl, C₆₋₁₀arylamino, carboxyC₆₋₁₀aryl,C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy, C₁₋₄alkoxysulfonyloxy,C₁₋₄alkylthio, C₁₋₄aminocarbonyloxy, C₁₋₄alkylsulfonylamino,C₁₋₄alkylcarbonylamino, C₁₋₄alkenylcarbonylamino,C₃₋₆cycloalkenylcarbonylamino, C₃₋₆cycloalkylcarbonylamino,C₁₋₄alkoxycarbonylamino, C₆₋₁₀arylcarbonylamino orC₆₋₁₀arylsulfonylamino, may further be optionally substituted with oneor more same or different substituents represented by hydroxy, halogen,C₁₋₄alkyl, C₁₋₃alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₆heterocycloalkyl,C₆₋₁₂aryl or oxo, wherein said C₁₋₄alkyl, C₁₋₃alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₆heterocycloalkyl or C₆₋₁₂aryl are optionallyfurther substituted with trifluoromethyl, halogen, C₁₋₄alkyl, C₁₋₃alkoxyor C₁₋₄alkoxycarbonyl.
 6. A compound according to claim 1, wherein Grepresents —C(O)NH₂, C₁₋₄aminocarbonyl, C₄₋₅heterocycloalkylcarbonyl,C₆₋₁₀arylaminocarbonyl, C₆₋₁₀arylsulfonylaminocarbonyl, wherein saidC₁₋₄aminocarbonyl, C₄₋₅heterocycloalkylcarbonyl, C₆₋₁₀arylaminocarbonylor C₆₋₁₀arylsulfonylaminocarbonyl, are optionally substituted with oneor more, same or different substituents selected from oxo, hydroxy,C₁₋₄alkyl, C₁₋₃alkoxy, C₁₋₃alkoxycarbonyl, C₄₋₅heterocycloalkyl,C₆₋₁₀aryl, wherein said C₁₋₄alkyl, C₁₋₃alkoxy, C₁₋₃alkoxycarbonyl,C₄₋₅heterocycloalkyl or C₆₋₁₀aryl are optionally substituted with one ormore, same or different substituents represented by halogen,trifluoromethyl, C₁₋₃alkoxy or C₁₋₃alkoxycarbonyl.
 7. A compoundaccording to claim 1, wherein G represents methylpiperazinylcarbonyl,cyclopropylaminocarbonyl, isopropylaminocarbonyl, propylaminocarbonyl,morpholinocarbonyl, dimethylaminocarbonyl, isobutylaminocarbonyl,ethylaminocarbonyl, N-methoxy-N-methylaminocarbonyl,methoxycarbonylmethyleneaminocarbonyl, methoxyethyleneaminocarbonyl,ethoxycarbonylphenyleneaminocarbonyl, dimethylmorpholinocarbonyl,morpholinopropylaminocarbonyl, ethoxycarbonylpiperidinocarbonyl,chlorobenzylaminocarbonyl, phenylhydroxyethylaminocarbonyl,ethoxycarbonylethyleneaminocarbonyl,trifluoromethylphenylenepiperazinylcarbonyl,hydroxyindanylaminocarbonyl,phenylmethoxycarbonylmethyleneaminocarbonyl,methoxyethylenepiperazinylcarbonyl, trifluorobenzylaminocarbonyl,methoxycarbonylbenzylaminocarbonyl, methylphenylenesulfonylaminocarbonylor carboxyphenylmethyleneaminocarbonyl.
 8. A compound according to claim1, wherein G represents phenyl optionally substituted with one or more,same or different substituents selected from —C(O)H, —C(O)NH₂, hydroxy,halogen, cyano, nitro, amidino, carboxy, trifluoromethyl, C₁₋₆alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄hydroxyalkyl, C₁₋₆amino, aminoC₁₋₃alkyl,iminomethyl, hydroxyiminomethyl, C₁₋₆haloalkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₃alkoxycarbamoyl, C₁₋₄aminocarbonyl,C₁₋₃alkylsulfonylaminocarbonyl, hydroxyaminocarbonyl,C₁₋₆heterocycloalkyloxy, C₁₋₆heterocycloalkylaminocarbonyl,C₃₋₆cycloalkylaminocarbonyl, C₆₋₁₀arylaminocarbonyl,C₁₋₁₀heteroarylaminocarbonyl, C₃₋₆cycloalkyl, C₁₋₆heterocycloalkyl,C₁₋₆heterocycloalkenyl, C₁₋₆heterocycloalkylcarbonyl,C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy, C₁₋₄alkoxysulfonyloxy,C₁₋₄alkylthio, C₁₋₆cycloalkenyl, C₁₋₄aminosulfonyl,C₁₋₄aminocarbonyloxy, C₁₋₄alkylsulfonylamino, C₁₋₁₀heteroaryl,C₆₋₁₀arylamino, C₆₋₁₀aryloxycarbonyl, C₆₋₁₀arylcarbonylamino,C₆₋₁₀arylsulfonylamino, C₁₋₄alkylcarbonylamino,C₁₋₄alkenylcarbonylamino, C₃₋₆cycloalkenylcarbonylamino,C₃₋₆cycloalkylcarbonylamino, C₁₋₄alkoxycarbonylamino,C₁₋₆heterocycloalkylcarbonylamino, C₁₋₄alkylsulfonyl orC₁₋₆heterocycloalkylsulfonyl, wherein said C(O)NH₂, C₁₋₆alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄hydroxyalkyl, C₁₋₆amino, aminoC₁₋₃alkyl,iminomethyl, hydroxyiminomethyl, C₁₋₆haloalkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₁₋₃alkoxycarbamoyl, C₁₋₄aminocarbonyl,C₁₋₃alkylsulfonylaminocarbonyl, hydroxyaminocarbonyl,C₁₋₆heterocycloalkyloxy, C₁₋₆heterocycloalkylaminocarbonyl,C₃₋₆cycloalkylaminocarbonyl, C₆₋₁₀arylaminocarbonyl,C₁₋₁₀heteroarylaminocarbonyl, C₃₋₆cycloalkyl, C₁₋₆heterocycloalkyl,C₁₋₆heterocycloalkenyl, C₁₋₆heterocycloalkylcarbonyl,C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy, C₁₋₄alkoxysulfonyloxy,C₁₋₄alkylthio, C₁₋₆cycloalkenyl, C₁₋₄aminosulfonyl,C₁₋₄aminocarbonyloxy, C₁₋₄alkylsulfonylamino, C₁₋₁₀heteroaryl,C₆₋₁₀arylamino, C₆₋₁₀aryloxycarbonyl, C₆₋₁₀arylcarbonylamino,C₆₋₁₀arylsulfonylamino, C₁₋₄alkylcarbonylamino,C₁₋₄alkenylcarbonylamino, C₃₋₆cycloalkenylcarbonylamino,C₃₋₆cycloalkylcarbonylamino, C₁₋₄alkoxycarbonylamino,C₁₋₆heterocycloalkylcarbonylamino, C₁₋₄alkylsulfonyl, orC₁₋₆heterocycloalkylsulfonyl are optionally further substituted with oneor more, same or different substituents selected from the groupconsisting of hydroxy, —NH₂, C₁₋₆amino, iminomethyl, hydroxyiminomethyl,carboxy, trifluoromethyl, halogen, oxo, mercapto, cyano, —C(O)NH₂,nitro, C₁₋₆alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄hydroxyalkyl,C₁₋₆haloalkyl, C₁₋₃alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₆heterocycloalkylcarbonyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl,C₁₋₆heterocycloalkyl, C₆₋₁₂aryl, C₁₋₁₀heteroaryl, C₁₋₃alkoxyC₆₋₁₀aryl,C₁₋₁₀heterocycloalkylaryl, C₁₋₆heterocycloalkenyl, —S(O)₂NH₂, —S(O)₂OH,C₁₋₆ureido, C₁₋₆thioureido, C₁₋₄alkylcarbonyloxy, C₁₋₄alkoxycarbonyloxy,C₁₋₄alkoxysulfonyloxy, C₁₋₄alkoxycarbamoyl, C₁₋₄aminocarbonyl,C₁₋₄alkylthio, C₁₋₄aminosulfonyl, C₁₋₄aminocarbonyloxy,C₁₋₄alkylsulfonylamino, C₆₋₁₂arylsulfonyl, C₆₋₁₀arylsulfonylamino,C₁₋₄alkylcarbonylamino or C₁₋₄alkylsulfonyl, wherein saidC₃₋₆cycloalkyl, C₁₋₆alkyl, C₁₋₃alkoxy, C₁₋₄alkoxycarbonyl,C₁₋₆heterocycloalkyl, C₆₋₁₀aryl or C₁₋₁₀heteroaryl may be furthersubstituted with carboxy, halogen, hydroxy, cyano, C₁₋₆heterocycloalkyl,one or more C₁₋₆alkyl, C₁₋₃alkoxy, C₁₋₃alkoxyC₁₋₃alkoxyC₁₋₄alkoxycarbonyl, C₁₋₃hydroxyalkl or C₆₋₁₀aryl.
 9. A compoundaccording to claim 8, wherein G represents phenyl substituted with oneor more same or different substituents selected from cyano, carboxy,—C(O)H, —C(O)NH₂, hydroxyl, halogen, amidino, iminomethyl,hydroxyiminomethyl, C₁₋₆alkyl, C₂₋₄alkynyl, aminoC₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkoxycarbonyl, C₁₋₄alkoxycarbamoyl, C₁₋₃aminocarbonyl,C₃₋₆cycloalkyl, C₁₋₆heterocycloalkyl, C₁₋₆heterocycloalkylcarbonyl,C₁₋₆heterocycloalkyloxy, C₁₋₃aminocarbonyloxy, C₁₋₁₀heteroaryl,C₆₋₁₀arylamino, C₆₋₁₀aryloxycarbonyl, C₁₋₃alkylsulfonylaminocarbonyl,hydroxyaminocarbonyl, C₁₋₃alkylsulfonyl, C₁₋₆heterocycloalkylsulfonyl,C₁₋₆heterocycloalkylaminocarbonyl, C₃₋₆cycloalkylaminocarbonyl,C₆₋₁₀arylaminocarbonyl, C₁₋₃aminosulfonyl, C₁₋₁₀heteroarylaminocarbonyl,C₁₋₃alkylcarbonylamino, C₁₋₃alkylsulfonylamino orC₆₋₁₀arylsulfonylamino, each of which is optionally substituted with oneor more same or different substituents selected from hydroxy, —NH₂,C₁₋₃amino, iminomethyl, carboxy, trifluoromethyl, cyano, fluoro, chloro,iodo, oxo, mercapto, C₁₋₄alkyl, C₁₋₃hydroxyalkyl, C₁₋₂alkoxy,C₁₋₄alkoxycarbonyl, C₃₋₆cycloalkyl, C₃₋₅heterocycloalkyl,C₁₋₆heterocycloalkylcarbonyl, C₆₋₁₀aryl, C₁₋₁₀heteroaryl,C₁₋₂alkoxyC₆₋₁₀aryl, C₁₋₃alkylsulfonylamino, —S(O)₂OH orC₁₋₃alkylcarbonylamino, wherein said C₃₋₆cycloalkyl, C₁₋₄alkyl,C₁₋₂alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₆heterocycloalkyl, C₆₋₁₀aryl orC₁₋₁₀heteroaryl are optionally further substituted with carboxy,halogen, hydroxy, cyano, C₁₋₆heterocycloalkyl, one or more C₁₋₆alkyl,C₁₋₃alkoxy, C₁₋₃alkoxyC₁₋₃alkoxy, C₁₋₄alkoxycarbonyl, C₁₋₃hydroxyalkylor C₆₋₁₀aryl.
 10. A compound according to any one of claim 8 or 9,wherein G represents phenyl substituted with iodo, fluoro,hydroxymethylpyrrolidinylcarbonyl, ethylaminocarbonyl,dimethylaminoethylmethylaminocarbonyl, pyrrolidinyliminomethyl, amidino,aminohydroxyiminomethyl, methoxycarbonyl, ethoxycarbonyl,hydroxyethylaminocarbonyl, N-hydroxyethyl-N-methylaminocarbonyl,N-hydroxymethyl-N-propylaminocarbonyl, bishydroxyethylaminocarbonyl,dihydroxytert-butylaminocarbonyl, N-hydroxyethyl-N-ethylaminocarbonyl,cyanoethylaminocarbonyl, morpholinoethylaminocarbonyl,fluoroethylaminocarbonyl, difluoroethylaminocarbonyl,methoxycarbonylethylaminocarbonyl,N-pyridylmethyl-N-methylaminocarbonyl, benzyloxycarbamoyl,methylcarbonylaminoethylaminocarbonyl, iodophenyleneoxycarbonyl,methoxyethylaminocarbonyl, mercaptoethylaminocarbonyl,ethoxycarbonylmethylaminocarbonyl, sulfoethylaminocarbonyl,dimethylaminocarbonyl, dimethylaminoethylaminocarbonyl,dimethylaminopropylaminocarbonyl, piperidinocarbonyl,methylpiperazinylcarbonyl, hydroxyethylpiperazinylcarbonyl,morpholinocarbonyl, hydroxypiperidinocarbonyl,imidazolylpropylaminocarbonyl, carboxymethylaminocarbonyl,tert-butoxycabonylmethoxycarbonylethylaminocarbonyl,tert-butoxycarbonylcarboxyethylaminocarbonyl,methoxycarbonylphenylethylaminocarbonyl,carboxyphenylethylaminocarbonyl,methoxycarbonylindolylethylaminocarbonyl,carboxyindolylethylaminocarbonyl,N-ethoxycarbonylmethyl-N-cyclohexylaminocarbonyl,diethoxycarbonylmethylaminocarbonyl,tert-butoxycarbonylhydroxyethylaminocarbonyl,carboxypyridylaminocarbonyl, carboxyphenylaminocarbonyl,methoxyethoxycarbonylphenylaminocarbonyl,N,N-dicarboxymethylaminocarbonyl, carboxycyclopentylmethylaminocarbonyl,carboxyethylaminocarbonyl, carboxymethylcyclohexylaminocarbonyl,ethylcarboxycyclopropylaminocarbonyl, carboxycyclopropylaminocarbonyl,carboxyisopropylaminocarbonyl, carboxyazetidinylcarbonyl,N-methyl-N-carboxymethylaminocarbonyl, carboxypropylaminocarbonyl,ethoxycarbonylpiperidylcarbonyl, carboxypiperidylcarbonyl,N-ethoxycarbonylmethyl-N-cyclohexylaminocarbonyl,N-carboxymethyl-N-cyclohexylaminocarbonyl,oxotetrahydrofurylaminocarbonyl, cyanomethylaminocarbonyl,cyanopyrazolaminocarbonyl,phenylmethoxycarbonylhydroxyethylaminocarbonyl,methoxycarbonylhydroxyethylaminocarbonyl,ethoxycarbonylhydroxyethylaminocarbonyl,carboxyhydroxyethylaminocarbonyl, carboxyhydroxypropylaminocarbonyl,tert-butoxyaminocarbonyl, methoxyaminocarbonyl,tetrahydrofurylmethoxyaminocarbonyl, N-methoxy-N-methylaminocarbonyl,phenylmethoxyaminocarbonyl, hydroxyaminocarbonyl,morpholinocarbonylmethoxyaminocarbonyl, methylsulfonylaminocarbonyl,methoxycarbonylhydroxypyrrolidinylcarbonyl,carboxyhydroxypyrrolidinylcarbonyl, ethoxycarbonylmethoxy,methoxycarbonylethyl, carboxymethoxy, carboxyethyl, ethoxycarbonylethyl,carboxymethoxy, oxopyrrolidinyl, oxooxazolidinyl, methylcarbonylamino,hydroxytetrahydropyranyl, imidazolyl, hydroxycyclopentyl, methylcarboxy,hydroxymethyl, hydroxycyclobutyl, diethoxycarbonylmethyl,ethoxycarbonylmethyl, carboxymethyl, fluorooxetanyl, aminomethylbutynyl,cyclopropyl[1,2,4]oxadiazolyl, cyclopentyl[1,2,4]oxadiazolyl,methyl[1,2,4]oxadiazolyl, isopropyl[1,2,4]oxadiazolyl,tert-butyl[1,2,4]oxadiazolyl, cyclohexyl[1,2,4]oxadiazolyl,methylbutyl[1,2,4]oxadiazolyl, dioxoimidazolidinyl[1,2,4]oxadiazolyl,methyloxazolyl[1,2,4]oxadiazolyl, dimethyloxazolyl[1,2,4]oxadiazolyl,cyanomethylethyl, carboxymethylethyl, methylsulfonyl, methoxycarbonyl,hydroxymethyl, methylsulfonylaminomethyl, morpholinylsulfonyl,methylcarboxyaminomethyl, hydroxyethylaminosulfonyl,methylsulfonylamino, morpholinylethoxycarbonyl,methoxyethoxyethoxycarbonyl, methoxyethoxyethoxyethoxycarbonyl,ethoxyethoxyethoxyethoxycarbonyl, dihydroxypropoxycarbonyl,tetrahydrofuranylmethoxycarbonyl, hydroxy, ethoxycarbonylpropoxy,carboxypropoxy, carboxyethoxy, oxodihydrofuranyloxy, ethoxyethoxy,ethoxycarbonylethoxy, cyanophenylmethoxy, pyridylmethoxy,pyrazolylethoxy, indolylethoxy, carboxymethylethoxycarboxyhydroxypropoxy, carboxyphenylmethoxy, hydroxymethylpropoxy,hydroxydiethylethoxy, dimethylaminocarbonyloxy, hydroxydiethylpropyl,hydroxymethylbutyl, dihydroxypropoxy, carboxyfluorophenylmethoxy,hydroxyethoxy, hydroxymethylpyrrolidinylmethyl,hydroxypyrrolidinylmethyl, ethoxycarbonylpyridylmethyl,methyltetrahydrofuranylmethylarainomethyl, carboxy, ethoxy orhydroxypropyl.
 11. A compound according to claim 9, wherein when Grepresents phenyl being further substituted, the substituent is attachedto the phenylene ring in the meta or para position from where the phenylring is attached to the cycloalkyl representing


12. A compound according to claim 1, wherein G representsC₁₋₁₀heteroaryl or C₁₋₆heterocycloalkyl and wherein said C₁₋₁₀heteroarylor C₁₋₆heterocycloalkyl is optionally substituted with carboxy,C₁₋₆alkyl, C₆₋₁₀aryl, C₁₋₃alkoxycarbonyl, which may further beoptionally substituted with trifluoromethyl, halogen, C₁₋₃alkyl,C₁₋₃alkoxy, C₁₋₁₀heteroaryl, wherein C₁₋₁₀heteroaryl may further besubstituted with C₁₋₃alkyl or oxo.
 13. A compound according to claim 12,wherein G represents fluorophenylene[1,2,4]oxadiazolyl,phenyl[1,2,4]oxadiazolyl, isopropyl[1,2,4]oxadiazolyl,trifluoromethylphenylene[1,2,4]oxadiazolyl, methyl[1,2,4]oxadiazolyl,methylthiazolylmethylene[1,2,4]oxadiazolyl, propyl[1,2,4]oxadiazolyl,oxopyridinylmethylene[1,2,4]oxadiazolyl,methoxyphenylene[1,2,4]oxadiazolyl, methylcarboxylmidazolyl,ethoxycarbonylthienyl, ethoxycarbonylfuryl, pyridyl, carboxythienyl orcarboxyfuryl.
 14. A compound according to claim 1, wherein G representsphenylamino or phenyloxy, optionally substituted with cyano, carboxy,C₁₋₄alkoxycarbonyl or trifluoromethyl.
 15. A compound according to claim1, wherein A represents 1-naphthyl, 2-naphthyl or phenyl, each of whichare optionally substituted as defined in claim 1 for the substitution ofC₆₋₁₄aryl representing A.
 16. A compound according to claim 1, whereinR₄ represents hydrogen, hydroxy, halogen or C₁₋₆alkyl.
 17. A compoundaccording to claim 1 wherein R₅ represents hydrogen or C₁₋₆alkyl.
 18. Acompound according to claim 1 wherein R₂, R₃, R₄ and R₅ representhydrogen.
 19. A compound according to claim 1, wherein R₁ representsmethyl.
 20. A compound according to claim 1, wherein G representsC₆₋₁₀aryl, C₁₋₃aminocarbonylC₆₋₁₀aryl or C₁₋₄alkylC₆₋₁₀aryl optionallysubstituted with carboxy, C₁₋₃alkoxy or C₁₋₃alkoxycarbonyl, A represents1-naphthyl, R₂, R₃, R₄ and R₅ represent hydrogen and R₁ representsmethyl.
 21. A compound according to claim 1 selected from the groupconsisting of 3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylicacid (compound 1000), cyclobutyl-((R)-1-naphthalen-1-yl-ethyl)-amine,hydrochloride (compound 1001),3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic aciddimethylamide (compound 1002),3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid amide(compound 1003),(4-Methyl-piperazin-1-yl)-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutyl]-methanone;hydrochloride (compound 1004),3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acidcyclopropylamide (compound 1005),3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acidisopropylamide (compound 1006),3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acidpropylamide (compound 1007),Morpholin-4-yl-[3((R)-1-naphthalen-1-yl-ethylamino)-cyclobutyl]-methanone(compound 1008),3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acidtert-butylamide (compound 1009),3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acidethylamide (compound 1010),3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acidmethoxy-methyl-amide; hydrochloride (compound 1011),[3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclobutyl]-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1012),((R)-1-Naphthalen-1-yl-ethyl)-{3-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]cyclobutyl}-amine;hydrochloride (compound 1013),[3-(3-Methyl-[1,2,4]oxadiazol-5-yl)-cyclobutyl]-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1014), ((R)-1-Naphthalen-1-ylethyl)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-cyclobutyl]-amine;hydrochloride (compound 1015),((R)-1-Naphthalen-1-yl-ethyl)-{3-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclobutyl}-amine;hydrochloride (compound 1016),{3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclobutyl}-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1017),3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid4-chloro-benzylamide (compound 1018),{[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-aceticacid methyl ester (compound 1019),3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(2-methoxy-ethyl)-amide (compound 1020),4-{[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-benzoicacid ethyl ester (compound 1021),(2,6-Dimethyl-morpholin-4-yl)-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclobutyl]-methanone(compound 1022),3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(3-morpholin-4-yl-propyl)-amide (compound 1023),1-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-piperidine-4-carboxylicacid ethyl ester (compound 1024),3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(2-hydroxy-2-phenyl-ethyl)-amide (compound 1025),3-{[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-propionicacid ethyl ester (compound 1026),[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutyl]-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone(compound 1027),{[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-phenyl-aceticacid methyl ester (compound 1028),3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid(2-hydroxy-indan-1-yl)-amide (compound 1029),[4-(2-Methoxy-ethyl)-piperazin-1-yl]-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutyl]-methanone(compound 1030),3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarboxylic acid2,3,6-trifluoro-benzylamide (compound 1031),3-({[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-methyl)-benzoicacid methyl ester (compound 1032),4-({[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-methyl)-benzoicacid methyl ester (compound 1033),{[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclobutanecarbonyl]-amino}-phenyl-aceticacid (compound 1034),((R)-1-Naphthalen-1-yl-ethyl)-(3-phenyl-cyclobutyl)-amine (compound 1035and compound 1036),{3-[3-(4-Fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopentyl}-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1037),((R)-1-Naphthalen-1-yl-ethyl)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-cyclopentyl]-amine;hydrochloride (compound 1038),[3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclopentyl]-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1039),((R)-1-Naphthalen-1-yl-ethyl)-{3-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopentyl}-amine;hydrochloride (compound 1040),[3-(3-Methyl-[1,2,4]oxadiazol-5-yl)-cyclopentyl]-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1041),{3-[3-(5-Methyl-thiazol-2-ylmethyl)-[1,2,4]oxadiazol-5-yl]-cyclopentyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1042),((R)-1-naphthalen-1-yl-ethyl)-[3-(3-propyl-[1,2,4]oxadiazol-5-yl)-cyclopentyl]-amine;hydrochloride (compound 1043a and 1043b),1-{5-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-[1,2,4]oxadiazol-3-ylmethyl}-1H-pyridin-2-one;hydrochloride (compound 1044),{3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopentyl}-((R)-1-naphthalen-1-yl-ethyl)-amine;hydrochloride (compound 1045),3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid amide(compound 1046),4-Methyl-N-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarbonyl]-benzenesulfonamide (compound 1047a, compound 1047b, compound1047c and compound 1047d),4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzonitrile(compounds 1048/1049/1050),N-Hydroxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamidine(compound 1051),N-Hydroxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamidine(compound 1052),N-Hydroxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamidine(compound 1053a and compound 1053b),{3-[4-(Imino-pyrrolidin-1-yl-methyl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1054),4-[3((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamidine (compound1055), 4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid(compound 1056),4-[3((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid(compound 1057),4-[3((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid(compound 1058, 1058a),3-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid ethylester (compound 1059),N-(2-Hydroxy-ethyl)-3-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1060),3-[3((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid(compounds 1061/1062), ((R)-1-Naphthalen-1-yl-ethyl)-(3(S)-phenyl-cyclohexyl)-amine (compound 1063),((R)-1-Naphthalen-1-yl-ethyl)-(3(R)-phenyl-cyclohexyl)-amine (compound1064), N—((R)-1-Naphthalen-1-yl-ethyl)-N-phenyl-cyclohexane-1,3-diamine(compound 1065),N—((R)-1-Naphthalen-1-yl-ethyl)-N-(3-trifluoromethyl-phenyl)-cyclohexane-1,3-diamine(compound 1066),4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexylamino]-benzonitrile(compound 1067),(3-Morpholin-4-yl-cyclohexyl)-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1068), ((R)-1-Naphthalen-1-ylethyl)-(3-pyridin-2-yl-cyclohexyl)-amine (compounds 1069/1070),5-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-thiophene-2-carboxylicacid ethyl ester (compound 1071),5-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-thiophene-2-carboxylicacid (compound 1072),5-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-furan-2-carboxylicacid ethyl ester (compound 1073),5-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-furan-2-carboxylicacid (compound 1074a, compound 1074b and compound 1074c),{3-[3-(4-Fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1075),((R)-1-Naphthalen-1-yl-ethyl)-{3-[3-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclohexyl}-amine(compound 1076),((R)-1-Naphthalen-1-yl-ethyl)-[3-(3-phenyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-amine(compound 1077),4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide (compound1078),N-Benzyloxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1079),4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid4-iodo-phenyl ester (compound 1080),2-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-ethanesulfonicacid (compound 1081),N—((R)-1-Hydroxymethyl-propyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1082),N—((S)-1-Hydroxymethyl-propyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1083),N-(2-Cyano-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1084),N-(2-Morpholin-4-yl-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1085),N-(2-Fluoro-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1086),N-(2,2-Difluoro-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1087),3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid methyl ester (compound 1088),N-Methyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-N-pyridin-4-ylmethyl-benzamide(compound 1089),N-(2-Dimethylamino-ethyl)-N-methyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1090),(2-Hydroxymethyl-pyrrolidin-1-yl)-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone(compound 1091),N-(2-Acetylamino-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1092),N-Ethyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1093),N-(2-Hydroxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1094),N-(2-Hydroxy-1-hydroxymethyl-1-methyl-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1095),N-(2-Methoxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1096),N-(2-Mercapto-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1097),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-aceticacid ethyl ester (compound 1098),N,N-Dimethyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1099),N-(2-Hydroxy-ethyl)-N-methyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1100),N-Ethyl-N-(2-hydroxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1101),N,N-Bis-(2-hydroxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1102),N-(2-Dimethylamino-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1103),N-(3-Dimethylamino-propyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1104),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-piperidin-1-yl-methanone(compound 1105),(4-Methyl-piperazin-1-yl)-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone(compound 1106),[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone(compound 1107),Morpholin-4-yl-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone(compound 1108),(4-Hydroxy-piperidin-1-yl)-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanone(compound 1109),N-(3-Imidazol-1-yl-propyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1110),3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentanecarboxylic acid(compound 1111),{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-aceticacid (compound 1115),(S)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-succinicacid 4-tert-butyl ester 1-methyl ester (compound 1116),(S)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-succinicacid 4-tert-butyl ester (compound 1117),(R)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionicacid methyl ester (compound 1118),(R)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionicacid (compound 1119),(S)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionicacid methyl ester (compound 1120),(S)-2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-3-phenyl-propionicacid; hydrochloride (compound 1121),(S)-3-(1H-Indol-3-yl)-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]benzoylamino}-propionicacid methyl ester (compound 1122),(S)-3-(1H-Indol-3-yl)-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid (compound 1123),(R)-3-(1H-Indol-3-yl)-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid methyl ester (compound 1124),(R)-3-(1H-Indol-3-yl)-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid (compound 1125),(Cyclohexyl-{4-[3-(1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-aceticacid ethyl ester (compound 1126),2-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-malonicacid diethyl ester (compound 1127),(S)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid tert-butyl ester (compound 1128),5-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-nicotinicacid (compound 1129),4-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-benzoicacid (compound 1130),4-Methoxy-3-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-benzoicacid methyl ester; hydrochloride (compound 1131),2-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-benzoicacid; hydrochloride (compound 1132),(Carboxymethyl-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-aceticacid; hydrochloride (compound 1133),1-({4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-methyl)-cyclopentanecarboxylicacid (compound 1134),1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-cyclopentanecarboxylicacid; hydrochloride (compound 1135),3-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid; hydrochloride (compound 1136),(1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]benzoylamino}-cyclohexyl)-aceticacid; hydrochloride (compound 1137),1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-cyclopropanecarboxylicacid ethyl ester (compound 1138),1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-cyclopropanecarboxylicacid (compound 1139),1-({4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-methyl)-cyclopropanecarboxylicacid (compound 1140),2-Methyl-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid (compound 1141),1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-azetidine-3-carboxylicacid (compound 1142),(Methyl-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-aceticacid (compound 1143),4-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-butyricacid (compound 1144),1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-piperidine-4-carboxylicacid ethyl ester (compound 1145),1-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-piperidine-4-carboxylicacid (compound 1146),(Cyclohexyl-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-aceticacid ethyl ester (compound 1147),(Cyclohexyl-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-amino)-aceticacid (compound 1148),4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-N-((R)-2-oxo-tetrahydro-furan-3-yl)-benzamide(compound 1149),N-Cyanomethyl-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1150),N-(4-Cyano-1H-pyrazol-3-yl)-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1151),(R)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid benzyl ester (compound 1152),(S)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid benzyl ester (compound 1153),(S)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid methyl ester (compound 1154),(R)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid methyl ester (compound 1155),(S)-3-Hydroxy-2-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid ethyl ester; hydrochloride (compound 1156),3-Hydroxy-2-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-propionicacid; hydrochloride (compound 1157),(R)-4-Hydroxy-2-{4-[(1S,33)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoylamino}-butyricacid (compound 1158),N-tert-Butoxy-4-[(1S,33)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide;formiate (compound 1159),N-tert-Butoxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide;formiate (compound 1160),N-Methoxy-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide;formiate (compound 1161),N-Methoxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide;formiate (compound 1162),4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-N-(tetrahydro-furan-3-ylmethoxy)-benzamide(compound 1163),4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-N-(tetrahydro-furan-3-ylmethoxy)-benzamide(compound 1164),N-Methoxy-N-methyl-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide;bis formate (compound 1165),N-Methoxy-N-methyl-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1166),N-Benzyloxy-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1167),N-Benzyloxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1168),N-Hydroxy-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1169),N-Hydroxy-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1170),N-(2-Morpholin-4-yl-2-oxo-ethoxy)-4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1171),N-(2-Morpholin-4-yl-2-oxo-ethoxy)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzamide(compound 1172),N-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-methanesulfonamide(compound 1173),4R-Hydroxy-1-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-pyrrolidine-2S-carboxylicacid methyl ester (compound 1174),4R-Hydroxy-1-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-pyrrolidine-2S-carboxylicacid (compound 1175),N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoyl}-methanesulfonamide;hydrochloride (compound 1176),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid ethyl ester (compound 1177/1178),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid ethyl ester (compound 1179/1180),3-{4-[(3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid methyl ester (compounds 1181/1182/1183/1184),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid (compound 1185),{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid (compound 1186),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid (compound 1187),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid (compound 1188),3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid (compound 1189),3-{4-[(1S,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid; hydrochloride (compound 1190),3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid (compound 1191),3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid (compound 1192),{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid ethyl ester (compounds 1193/1194/1195/1196),3-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid ethyl ester (compounds 1197/1198/1198/1200),{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid hydrochloride (compound 1201),{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid (compound 1202),{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid (compound 1203),3-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid hydrochloride (compound 1204),3-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid (compound 1205),3-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid (compound 1206),3-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid (compound 1207),3-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid hydrochloride (compound 1208),[3-(4-Iodo-phenyl)-cyclohexyl]-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1209),1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-pyrrolidin-2-one(compound 1210),3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-oxazolidin-2-one(compound 1211),N-{4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-acetamide(compound 1212),4-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-tetrahydro-pyran-4-ol(compound 1213),[3-(4-Imidazol-1-yl-phenyl)-cyclohexyl]-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1214),1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-cyclopentanol(compound 1215),1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]phenyl}-ethanone(compound 1216),4-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-tetrahydro-pyran-4-olhydrochloride (compound 1217),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanol(compound 1218),1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-cyclobutanol(compound 1219),2-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]phenyl}-malonicacid diethyl ester (compound 1220),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-acetic acidethyl ester (compound 1221),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-acetic acid(compound 1222),3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-oxetan-3-ol(compound 1223),{3-[4-(3-Fluoro-oxetan-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1224),{3-[4-(3-Amino-3-methyl-but-1-ynyl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1225),{3-[4-(5-Cyclopropyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1226),{3-[4-(5-Cyclopentyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1227),{3-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1228),{3-[4-(5-Isopropyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1229),{3-[4-(5-tert-Butyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1230),{3-[4-(5-Cyclohexyl-[1,2,4]oxadiazol-3-yl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1231),(3-{4-[5-(3-Methyl-butyl)-[1,2,4]oxadiazol-3-yl]-phenyl}-cyclohexyl)-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1232),5-(3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-[1,2,4]oxadiazol-5-ylmethyl)-imidazolidine-2,4-dione(compound 1233),(3-{4-[5-(4-Methyl-oxazol-5-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-cyclohexyl)-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1234),(3-{4-[5-(2,5-Dimethyl-oxazol-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-cyclohexyl)-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1235),2-Methyl-2-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-propionitrile(compound 1236/1237),2-Methyl-2-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-propionicacid (compound 1238),2-Methyl-2-{4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-propionicacid (compound 1239),[3-(4-Methanesulfonyl-phenyl)-cyclohexyl]-((R)-1-naphthalen-1-yl-ethyl)-amine(compounds 1240),2-Fluoro-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid methyl ester (compound 1241),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanol(compound 1242),N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-methanesulfonamide(compound 1243),{3-[4-(Morpholine-4-sulfonyl)-phenyl]-cyclohexyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1244/1245),N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-acetamide(compounds 1246/1247),3-Fluoro-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoicacid methyl ester (compound 1248),N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanesulfonamide(compound 1249/1250),N-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenyl}-methanesulfonamide(compound 1251),N-(2-Hydroxy-ethyl)-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclohexyl]-benzenesulfonamide(compounds 1252/1253),3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]phenyl}-propionicacid (compound 1254),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-phenoxy}-aceticacid (compound 1255),[3-(4-Methanesulfonyl-phenyl)-cyclopentyl]-((R)-1-naphthalen-1-yl-ethyl)-amine(compounds 1256/1257),N-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-methanesulfonamide(compounds 1258/1259),N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-acetamide(compounds 1260/1261),N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzyl}-acetamide(compound 1262/1263),N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzyl}-methanesulfonamide(compounds 1264/1265),N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-methanesulfonamide(compounds 1266/1267),[3-(4-Methanesulfonyl-phenyl)-cycloheptyl]-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1268),2-Fluoro-4-[3-((R)-1-naphthalen-1-yl-ethylamino)-cycloheptyl]-benzoicacid methyl ester (compound 1269),N-{3-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-methanesulfonamide(compound 1270),N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-acetamide(compound 1271/1272),N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-benzyl}-acetamide(compounds 1273/1274),N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-benzyl}-methanesulfonamide(compounds 1275/1276),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenoxy}-aceticacid ethyl ester (compound 1277),3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-propionicacid methyl ester (compounds 1278/1279),N-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-methanesulfonamide(compounds 1280/1281),{3-[4-(Morpholine-4-sulfonyl)-phenyl]-cycloheptyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1282),{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cycloheptyl]-phenyl}-methanol(compound 1283),4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid methylester (compound 1284),4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid ethylester (compound 1285),4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid2-morpholin-4-yl-ethyl ester dihydrochloride (compound 1286),4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid2-(2-methoxy-ethoxy)-ethyl ester hydrochloride (compound 1287),4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester hydrochloride (compound1288), 4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid2-[2-(2-ethoxy-ethoxy)-ethoxy]-ethyl ester hydrochloride (compound1289), 4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acid2,3-dihydroxy-propyl ester hydrochloride (compound 1290),4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzoic acidtetrahydro-furan-2-ylmethyl ester hydrochloride (compound 1291),4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenol(compound 1292),2-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-butyricacid ethyl ester (compound 1293),2-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-butyricacid (compound 1294),2-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propionicacid (compound 1295),3-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-dihydro-furan-2-one(compound 1296),(S)-{3R-[4-(2-Ethoxy-ethoxy)-phenyl]-cyclopentyl}-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1297),3-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propionicacid ethyl ester (compound 1298),4-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxymethyl}-benzonitrile(compound 1299),(S)—((R)-1-Naphthalen-1-yl-ethyl)-{3R-[4-(pyridin-3-ylmethoxy)-phenyl]-cyclopentyl}-amine(compound 1300),(S)—((R)-1-Naphthalen-1-yl-ethyl)-{3R-[4-(2-pyrazol-1-yl-ethoxy)-phenyl]-cyclopentyl}-amine(compound 1301),(S)-(3R-{4-[2-(1H-Indol-3-yl)-ethoxy]-phenyl}-cyclopentyl)-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1302),2-Methyl-2-{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propionicacid hydrochloride (compound 1303),4-Hydroxy-2-{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]phenoxy}-butyricacid (compound 1304),2-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propionicacid hydrochloride (compound 1305),{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-phenyl-aceticacid hydrochloride (compound 1306),2-Methyl-1-{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propan-2-ol(compound 1307),3-{4-[(1R,38)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxymethyl}-pentan-3-ol(compound 1308), Dimethyl-carbamic acid4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenylester (compound 1309),3-Ethyl-1-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-pentan-3-ol(compound 1310),2-Methyl-4-{4-[(1S,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-butan-2-ol(compound 1311),3-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-propane-1,2-diol(compound 1312),(2-Fluoro-phenyl)-{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-aceticacid hydrochloride (compound 1313),2-{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-ethanolformiate (compound 1314),(1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-pyrrolidin-2-yl)-methanol(compound 1315),1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-pyrrolidin-3-ol(compound 1316),1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexyl]-benzyl}-piperidine-3-carboxylicacid ethyl ester (compound 1317),[3-(4-{[Methyl-(tetrahydro-furan-2-ylmethyl)-amino]-methyl}-phenyl)-cyclohexyl]-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1318),3-(4-{(1S,3S)-3-[(R)-1-(4-Fluoro-3-methoxy-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid ethyl ester (compound 1319),3-(4-{(1S,3S)-3-[(R)-1-(3-Cyano-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid ethyl ester (compound 1320),3-{4-[(1S,3S)-3-((R)-1-Benzo[b]thiophen-3-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid ethyl ester (compound 1321),3-(4-{(1S,38)-3-[(R)-1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid ethyl ester (compound 1322),3-{4-[(1S,3S)-3-((R)-1-Phenyl-ethylamino)-cyclopentyl]-phenyl}-propionicacid ethyl ester (compound 1323),3-(4-{(1S,3S)-3-[(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid ethyl ester (compound 1324),3-(4-{(1S,3S)-3-[(R)-1-(1H-Indol-7-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid hydroformiate (compound 1325),3-(4-{(1S,3S)-3-[(R)-1-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid hydroformiate (compound 1326),3-(4-{(1S,3S)-3-[(R)-1-(1H-Indol-4-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid hydroformiate (compound 1327),3-(4-{(1S,3S)-3-[(R)-1-(3-Cyano-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid, hydroformiate (compound 1328),3-(4-{(1S,3S)-3-[(R)-1-(3-Pyrrolidin-1-yl-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid hydroformiate (compound 1329),3-(4-{(1S,3S)-3-[(R)-1-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid hydroformiate (compound 1330),3-(4-{(1S,38)-3-[(R)-1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid (compound 1331), 3-(4-{(1S,[(R)-1-(4-fluoro-3-methoxy-1-yl-phenyl)-ethylamino]-cyclopentyl}-phenyl)-propionicacid (compound 1332),3-{4-[(1S,3S)-3-((R)-1-Benzo[b]thiophen-3-yl-ethylamino)-cyclopentyl]-phenyl}-propionicacid, hydrochloride (compound 1333),3-{4-[(1S,3S)-3-((R)-1-Phenyl-ethylamino)-cyclopentyl]-phenyl}-propionicacid (compound 1334),4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoic acid ethylester (compound 1335/1336),4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoic acid(compound 1337),4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoic acid(compound 1338),3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoylamino}-propionicacid methyl ester (compound 1339),1-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoyl}-piperidine-4-carboxylicacid hydrochloride (compound 1340),3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-benzoylamino}-propionicacid hydrochloride (compound 1341),4-[3((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyloxy]-benzoic acidmethyl ester (compound 1342),4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyloxy]-benzoic acidformiate (compound 1343),5-Methyl-3-[3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-3H-imidazole-4-carboxylicacid (compound 1344),(3S,4S-Diphenyl-cyclopentyl)-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1345),5-(4-ethoxy-phenyl)-2-propyl-cyclohexyl]-((R)-1-naphthalen-1-yl-ethyl)-amine(compound 1346)[2-(4-Fluoro-phenyl)-54(R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-aceticacid hydrochloride (compound 1347), or3-{4-[3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenyl}-propan-1-ol(compound 1348).
 22. An intermediate for the preparation of compoundsaccording to claim 1 selected from the group consisting of3-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclobutanone(compound 1112),4-methyl-N-(3-oxo-cyclopentanecarbonyl)-benzenesulfonamide (compound1113), 3-(3-trifluoromethylphenyl)amino-cyclohexanone (compound 1114),3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclohexanecarboxylic acid(preparation 4), 3-(4-Iodophenyl)-cyclohexan-1-one (preparation 5),4-(3-Oxo-cyclohexyl)-benzaldehyde (preparation 7),3-[4((1S)-3-Oxo-cyclopentyl)-phenyl]-propionic acid ethyl ester(preparation 8), 3-[4-((1S,3R)-3-Acetoxy-cyclopentyl)-phenyl]-propionicacid ethyl ester (preparation 9),3-[4-((1S,3R)-3-Hydroxy-cyclopentyl)-phenyl]-propionic acid ethyl ester(preparation 10),3-[4-((1S,3R)-3-Methanesulfonyloxy-cyclopentyl)-phenyl]-propionic acidethyl ester (preparation 11),4-((1S,45)-4-Acetoxy-cyclopent-2-enyloxy)-benzoic acid methyl ester(preparation 13), 4-((1S,4S)-4-Hydroxy-cyclopent-2-enyloxy)-benzoic acidmethyl ester (preparation 14),4-((1S,4R)-4-Chloro-cyclopent-2-enyloxy)-benzoic acid methyl ester(preparation 15),4-[(1S,4S)-4-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopent-2-enyloxy]-benzoicacid methyl ester (preparation 16),3-((1S,4S)-4-Acetoxy-cyclopent-2-enyl)-5-methyl-3H-imidazole-4-carboxylicacid ethyl ester (preparation 17),3-((1S,4S)-4-Hydroxy-cyclopent-2-enyl)-5-methyl-3H-imidazole-4-carboxylicacid ethyl ester (preparation 18),3-((1S,4R)-4-Chloro-cyclopent-2-enyl)-5-methyl-3H-imidazole-4-carboxylicacid ethyl ester (preparation 19) or5-Methyl-3-[(1S,4S)-4-((R)-1-naphthalen-1-yl-ethylamino)-cyclopent-2-enyl]-3H-imidazole-4-carboxylicacid ethyl ester (preparation 20).
 23. A compound according to claim 1for use as a medicament in therapy.
 24. A compound according to claim 1or compound N-cyclopentyl-α-methyl-benzenemethanamine,N-cyclohexyl-α-methyl-benzenemethanamine,3-[3-[(1-phenylethyl)amino]cyclohexyl]-phenol,2-[3-[3-[(1-phenylethyl)amino]cyclohexyl]phenoxy]-, ethyl ester, aceticacid,N-[3-(3-methoxyphenyl)cyclohexyl]-α-methyl-2-naphthalenemethanamine,N-[3-(3-methoxyphenyl)cyclohexyl]-α-methyl-benzenemethanamine,N-cyclohexyl-α-methyl-1-naphthalenemethanamine,4-chloro-N-cyclohexyl-α-methyl-benzenemethanamine, orN-(1-phenylethyl)-cycloheptanamine, for use in the treatment,amelioration or prophylaxis of physiological disorders or diseasesassociated with disturbances of CaSR activity, such ashyperparathyroidism.
 25. Use of a compound according to claim 1 orcompound N-cyclopentyl-α-methyl-benzenemethanamine,N-cyclohexyl-α-methyl-benzenemethanamine,3-[3-[(1-phenylethyl)amino]cyclohexyl]-phenol,2-[3-[3-[(1-phenylethyl)amino]cyclohexyl]phenoxy]-, ethyl ester, aceticacid,N-[3-(3-methoxyphenyl)cyclohexyl]-α-methyl-2-naphthalenemethanamine,N-[3-(3-methoxyphenyl)cyclohexyl]-α-methyl-benzenemethanamine,N-cyclohexyl-α-methyl-1-naphthalenemethanamine,4-chloro-N-cyclohexyl-α-methyl-benzenemethanamine, orN-(1-phenylethyl)-cycloheptanamine, for the manufacture of a medicamentfor the prophylaxis, treatment or amelioration of physiologicaldisorders or diseases associated with disturbances of CaSR activity,such as hyperparathyroidism.
 26. A pharmaceutical composition comprisinga compound according to claim 1 or a pharmaceutically acceptable salt,solvate, or in vivo hydrolysable ester thereof together with apharmaceutically acceptable vehicle or excipient.
 27. A method ofpreventing, treating or ameliorating parathyroid carcinoma, parathyroidadenoma, primary parathyroid hyperplasia, cardiac, renal or intestinaldisfunctions, diseases of the central nervous system, chronic renalfailure, chronic kidney disease, podocyte-related diseases, primaryhyperparathyroidism, secondary hyperparathyroidism, tertiaryhyperparathyroidism, anemia, cardiovascular diseases, osteitis fibrosa,adynamic bone disease, osteoporosis, steroid induced osteoporosis,senile osteoporosis, post menopausal osteoporosis, osteomalacia andrelated bone disorders, bone loss post renal transplantation,gastrointestinal diseases, endocrine and neurodegenerative diseases,cancer, Alzheimer's disease, hypercalcemia, or renal bone diseases, themethod comprising administering to a patient in need thereof aneffective amount of a compound according to claim 1, optionally incombination or as supplement with an active vitamin-D sterol orvitamin-D derivative, such as 1-α-hydroxycholecalciferol,ergocalciferol, cholecalciferol, 25-hydroxycholecalciferol,1-α-25-dihydroxycholecalciferol, or in combination or as supplement withphosphate binders, estrogens, calcitonin or biphosphonates.